6,9-disubstituted 2-[trans-(4-aminocyclohexyl) amino] purines

ABSTRACT

The present invention comprises 6-9-Disubstituted 2-[trans-(4-aminocyclohexyl]aminopurines that are useful in inhibiting cyclin dependent kinases, particularly cdk-2. The present invention also provides a method of preventing apoptosis in neuronal cells and a method of inhibiting the development of neoplasms.

[0001] This application is a continuation of application Ser. No.09/247,053 filed Feb. 9, 1999, now allowed, which claims the benefit ofprovisional application No. 60/135,109, filed Feb. 26, 1998.

[0002] The present invention relates to 6,9-disubstituted2-[trans-(4-aminocyclohexyl)amino]purines and methods of using the samefor antineoplastic agents or for treatment for neuronal injury anddegeneration.

BACKGROUND OF THE INVENTION

[0003] Cell division, in both normal and neoplastic cells, is a tightlycontrolled event which occurs by defined stages. Quiescent cells whichare not actively dividing, are in the G₀ phase, as are those terminallydifferentiated or in a state of temporary arrest. The first phase is thefirst gap (G₁) phase during which the cell prepares to synthesize DNA.In late G₁ phase at what is termed a restriction point or R point, thecell commits to entering S phase during which DNA synthesis occurs. Uponcompletion of S phase, the cell enters the second gap (G₂) phase duringwhich the cell prepares to divide, which is followed by mitosis, or Mphase.

[0004] Initial experiments in cell cycle regulation revealed theexistence of a protein called “Maturation Promoting Factor” (MPF), aheterodimer with kinase activity. Later, comparison of subsequentlyidentified proteins and their underlying genes revealed a family ofyeast genes known as cell division control (cdc) genes. Furtherexperiments demonstrated that some of the cdc genes encode kinases, andwere later called cyclin-dependent kinases (cdks). As the result of thisreclassification, some cell cycle proteins have dual designations, suchas cdk1 which is also known as cdc2. The kinase component of the MPF isnow identified as p34^(cdc2) and the regulatory subunit of MPF is nowcalled cyclin B. Cyclins were first identified as proteins whose levelsoscillated during the cell cycle and were specifically degraded atmitosis. To date, animal cyclins A-I and cdks 1-8 have been identified.To further complicate nomenclature, subtypes of cyclins and cdks havebeen identified, such as cyclins B1 and B2.

[0005] Subsequent research on cell regulation has demonstrated that thestages of cellular division are achieved in part by modulation cyclinsand cyclin-dependent kinases (cdks). Cyclins sequentially regulate cdksand are characterized by a 100 amino acid homology region termed the“cyclin box” which is involved in binding a protein kinase partner. Cdksare closely related in sequence and size (35-40 kDa) and are defined asprotein kinases activated by bound cyclin regulatory subunits. Cdkscontain a conserved active-site cleft of approximately 300 amino acidsthat is characteristic of all eukaryotic protein kinases. Thus, both thecyclins and cdks appear to be highly conserved protein families.

[0006] Isolation of individual cyclins and cdks has enabled furtheridentification of the roles and interactions of each component in cellcycle phase transitions. Excess levels of cdks persist throughout thecell cycle. Activation of cdks occurs upon cyclin synthesis and bindingto the catalytic cdk subunit, the result of which is stimulation of thecdk serine/threonine kinase activity. Complete cdk activation requiresphosphorylation on a conserved threonine residue located in the T-loopby a cyclin-dependent kinase activating kinase (CAK), which is itself acdk/cyclin complex composed of cyclin H and cdk7, and a third protein ofabout 32 kDa.

[0007] Inactivation of the cdk-cyclin complex can result from thephosphorylation of a threonine and/or tyrosine residue in theATP-binding site of the cdk or from binding of one of a number ofendogenous inhibitor proteins.

[0008] In G₁ phase, D-type cyclins bind to several different cdks,including cdk2, cdk4, cdk5 and cdk6, but are most commonly associatedwith cdk4 and cdk6. D-type cyclins are thought to act as growth factorsensors, which link cell cycle progression to external cues. CyclinE-cdk2 complexes appear in the mammalian cell cycle after the D-typecyclin-cdk complexes. Cyclin E synthesis is tightly regulated and occursin late G₁ and early S phase. The cyclin E-cdk2 complex is essential forthe cell to begin DNA replication.

[0009] The G₁ cyclins, cyclin D and cyclin E, are transiently producedproteins, with a half-life of about 20 minutes. The short half-life isthought to result from a PEST sequence in the C-terminal regions ofthese proteins, the degradation of which appears to be mediated by theubiquitination pathway.

[0010] The G₂ cyclins, cyclin A and cyclin B, are stable throughoutinterphase and specifically destroyed at mitosis through anubiquitination pathway. Both cyclin A and cyclin B2 appear to bedegraded only when complexed with their cdk partner [cyclinA-cdk2 andcyclin A/B-cdk1 (cdc2)]. However, cyclin B1 destruction is connectedwith the integrity of the mitotic apparatus at the end of metaphase. Ifthe spindle is incorrectly assembled, or chromosomes incorrectlyaligned, then cyclin B1 destruction is prevented.

[0011] Retinoblastoma protein (Rb), a 105 kDa nuclear phosphoprotein, isa substrate of cyclin-cdk complexes of cdks-2, 4 and 6 in G₁ phase andfunctions as one of the major checkpoint controls in the cell cycle viacarefully orchestrated phosphorylation and dephosphorylation. In G₀/G₁,Rb exists in a hypophosphorylated state. As the cell progresses intolate G₁, Rb becomes hyperphosphorylated by D-cyclin complexes, whichinactivates Rb and drives the cell into S phase resulting in cell cycleprogression and cell division. This state of hyperphosphorylation of Rbremains in G₂. During late M phase, Rb is dephosphorylated, thusreturning to the hypophosphorylated state. Phosphorylation of the Rbprotein alters its binding characteristics; in the hypophosphorylatedstate, Rb binds to and sequesters specific transcription factors, suchas E2F, the binding of which prevents the exit from the G₁ phase. Oncecdks hyperphosphorylate Rb, the transcription factors are released whichcan then activate transcription of genes necessary for S phaseprogression, for example, thymdine kinase, myc, myb, dihydrofolatereductase, and DNA polymerase-α.

[0012] Localization of cyclin-CDK complexes is also very suggestiveabout the role each complex plays in the pathway. Nuclear cyclins A andE bind to p107 and p130, possibly because they are in the nucleus.Mammalian cyclin B1 accumulates in the cytoplasm in G₂ phase andtranslocates into the nucleus at the beginning of mitosis. Cyclin Bassociates with the spindle apparatus, in particular with the spindlecaps, and it is thought that the cyclin B-cdc2 kinase may be involved inthe formation of the spindle through phosphorylating components of themitotic apparatus. In addition, cyclin B1 is part of a feedbackmechanism ensuring correct assembly of the metaphase mitotic apparatus.Human cyclin B2 is almost exclusively associated with the membranecompartment, and in particular the Golgi apparatus. Cyclin B2-cdc2 isinvolved in the disassembly of the Golgi apparatus when cells entermitosis.

[0013] Cdc2-cyclin B kinase is a key mitotic factor which appears to behighly conserved and is thought to be involved in cell cycle transitionsin all eukaryotic cells. Histone H1 is a substrate for cdc2-cyclin B;histone H1 is selectively phosphorylated on specific sites in mitosis,which is thought to be important for chromatin condensation. Thecdc2-cyclin B complex also phosphorylates lamin, which is responsiblefor nuclear lamina breakdown. The nuclear lamina is made up of a polymerof lamin subunits that are hyperphosphorylated at mitosis, and thisphosphorylation is responsible for their disassembly. Lamins are part ofthe intermediate filament family of proteins, and cdc2-cyclin Bphosphorylates a subset of the sites phosphorylated at mitosis on thecytoplasmic intermediate filament subunits, vimentin and desmin. Thus,the cdc2-cyclin B complex is involved in the reorganization of the cellarchitecture at mitosis.

[0014] In addition, cdc2-cyclin B is involved in the reorganization ofmicrofilaments, through phosphorylation of non-muscle caldesmon, an 83kDa protein that binds to actin and calmodulin, and inhibits actomyosinATPase activity. At mitosis, caldesmon is phosphorylated by cdc2-cyclinB, which weakens its affinity for actin and causes it to dissociate frommicrofilaments.

[0015] Cdc2-cyclin B is implicated in actomyosin filament regulation, byphosphorylating the myosin in the contractile ring, which divides thecell into two (cytokinesis). In metaphase, the myosin II regulatorylight chain (MLC) is phosphorylated on two main sites at the N-terminus.Once phosphorylated, the myosin is prevented from interacting withactin. At anaphase, these two sites are dephosphorylated.

[0016] Cdc2-cyclin B also plays a role in reorganization of the membranecompartment at mitosis. For example, cdc2-cyclin B phosphorylates rab1Apand rab4p. When rab4p is phophorylated by cdc2-cyclin B, it dissociatesfrom the membrane compartment.

[0017] At mitosis, most forms of transcription are inhibited. Again,cdc2-cyclin B plays a role in inhibition of pol III-mediatedtranscription by phosphorylating TFIIIB. Given that pol I, pol II andpol III-mediated transcription share several common factors, such asTATA-binding protein (TBA), it is likely that cdc2-cyclin B is involvedin down-regulating all forms of transcription at mitosis.

[0018] Given the importance of cyclin/cdk complexes in triggering cellcycle division, they are under tight regulatory mechanisms. Since theirinitial discovery, cyclins and cdks have been shown to interact withother transcription factors and proteins involved in a broad range ofcellular pathways. Cdk7 has been identified as a component intranscription factor IIH (TFIIH), which contains the RNA polymerase IIC-terminal domain (CTD) kinase activity. More recently, cdk8 whichpartners with cyclin C, has also been discovered to phosphorylate theCTD of RNA polymerase II, but does not appear to possess CAK activity.Thus, it is clear that cdks participate in a broad range of cellularfunctions in addition to cell cycle regulation. CDK-inhibitor proteins(CDIs) are small proteins that bind and inactivate specific cyclin-CDKcomplexes, or monmeric CDKs. These inhibitors can be grouped into twofamilies based on sequence and functional similarities. The INK4 familyincludes p15^(INK4B), p16^(INK4), p18 and p19 which specifically bindcdk4 and cdk6. p16^(INK4) and p15^(INK4B) contain four ankyrin repeatsand, in addition to sharing significant homology, are encoded byadjacent genes on the 9p12 locus.

[0019] High cellular levels of p16 results in inactivation of cdk4because p16 binds cyclinD-cdk4 and cyclin D-cdk6 complexes. The gene forp16^(INK4) (MTS1) is recognized as a potential tumor suppressor gene, asit is rearranged, deleted or mutated in a large number of tumor celllines, and in some primary tumors. In one study of hereditary melanoma,about half the families had germline mutations in the p16^(INK4) gene.Rb is a repressor of p16^(INK4). Inactivation of cellular Rb, either bymutation or viral antigens, correlates with increased levels ofp16^(INK4). P16^(INK4), p₁₅ ^(INK4B), and p18 inhibit binding of cyclinD with cdk4 and cdk6.

[0020] The second family of CDIs is the Kip/Cip family which includesp₂₁ ^(Cip1, WAF-1), p27^(Kip1) and p57^(Kip2). p27^(KIP1) is present inproliferating cells in a latent or masked form. Upon stimulation,p27^(KIP1) is unmasked and binds to and inhibits cyclin-CDK4/6complexes. The Kip/Cip family proteins have strong homology in theN-terminus, the region that binds the cyclin-cdk complexes. The Kip/Cipfamily proteins preferentially bind to and inhibits cyclin-cdk complexesinvolved in the G₁ and S phase complexes over those involved in the Mphase.

[0021] P21 (also known as WAF1, Cip1 and Sdi1) is induced by p53 andforms a ternary complex with proliferating cell nuclear antigen (PCNA),a subunit of DNA polymerase δ in several cyclin-CDK2 complexes,including cyclins A, D1 and E. P21^(WAF-1) expression in growing,quiescent and senescent cells correlates with a role as a negativeregulator of S phase entry. P21^(WAF-1) mRNA is upregulated as cellsbecome senescent or quiescent, and after serum stimulation of quiescentcells, and decreases as cells enter S phase. p21 inactivates cyclinE-cdk2, cyclin A-cdk2, and cyclins D1-, D2- and D3-cdk4 complexes.

[0022] Genetic analysis of numerous human tumors reveals adisproportionate numer of altered cell cycle proteins, and it is thisaberration that is thought to cause abnormal cell cycle. For example,cyclin D1 is the bcl-1/PRAD1 proto-oncogene that is either overexpressedor deregulated in a variety of human tumors. The cyclin D1/CCND1 gene,located at chromosome 11q13, is amplified in a number of cancers, mainlybreast and non-small cell lung carcinomas. This correlates with theobservation that overexpression of cyclin D1 is a common feature in thetumors with this specific 11q13 amplicon. The gene for p16 isrearranged, deleted or mutated in a large number of tumour cell lines,and in some primary tumours. Mutations in cdk4, specifically an Arg24Cysmutation, has been identified in two unrelated hereditary melanomafamilies. This mutation was found in 11/11 of the melanoma patients,2/17 unaffecteds and 0/5 spouses (Zuo, L., et al., Nature Genetics 121996:97-99). This mutation has a specific effect on the p16^(INK4a)binding domain of cdk4, but has no affect on the ability to bind tocyclin D and form a functional kinase. As a result of this mutation, thecyclin D/cdk4 complex is resistant to normal physiological inhibition byp16^(INK4a). Other studies have demonstrated that about half thefamilial melanoma kindreds show evidence of linkage to the region ofchromosome 9p21 that contains the p16^(INK4a) gene. The types ofp16^(INK4a) mutations identified include a nonsense mutation, splicedonor mutation, an unidentified mutation that prevents p16^(INK4a)transcription, and 3 missense mutants that are unable to bind to cdk4 orcdk6. Overexpression of cdk4 as a result of gene amplification has beenidentified in a study of 32 glioma cell lines (He, J., et al., CancerRes. 54:5804-5807, 1994). This alteration was observed among the tencases having intact p16 genes. Genetic analysis of glioma cell linesrevealed that 24 of 32 glioma cell lines had one of two alternativegenetic alterations, each of which indicates that increased cdk4 kinaseactivity is important to glial tumor development. Cdk4 maps to the longarm of chromosome 12 and is found overexpressed in certain tumorsbecause of its amplification as a component of an amplicon that includesother relevant genes, such as SAS and MDM2. All of the above conditionslead to activation of cdk4. Overexpression of cyclins B1 and E inleukemic and solid tumor cell lines, as well as altered patterns ofcyclin E expression in breast cancer has also been reported.

[0023] Cellular hyperproliferation occurs in a number of disease states.The most common hyperproliferative diseases are neoplasms, which aretypically named according to the original source of thehyperproliferative tissue. Neoplasms are defined as new growths ofanimal or plant tissue that resemble more or less the tissue from whichit arises, but serve no physiologic function, and are benign,potentially malignant or malignant in character. Neoplasms arise as theresult of loss of normal controls, leading to unregulated growth.Neoplastic cells may lack differentiation and acquire the ability toinvade local tissues and metastasize. Neoplasms may develop in any typeof tissue of any organ at any age. The incidence, and mortality rate, ofneoplasms generally increases with age, with certain neoplasms havingpeak incidence between the ages of 60 and 80 (e.g. prostate, stomach andcolon). However, other neoplasms have a peak incidence from birth to 10years of age (e.g. acute lymphoblastic leukemia). Diet, exposure tocarcinogens, particularly use of tobacco, and familial predispositionsalso affect incidence of particular neoplasms.

[0024] Neoplastic cells differ from normal cells in a number ofimportant aspects, including loss of differentiation, increasedinvasiveness and decreased drug sensitivity. Another importantdifference is the unchecked growth of cells, which is thought to resultfrom loss of normal cellular control mechanisms of these cells areeither deactivated, bypassed or otherwise disregarded, leaving theneoplastic cells to proliferate without regard to the normal controllingmechanisms.

[0025] Neoplasm is an abnormal mass of tissue, the growth of whichexceeds and is uncoordinated with that of the normal tissue, andpersists in the same excessive manner after cessation of the stimuliwhich evoked the change.

[0026] Neoplasms are classified as either benign or malignant. Benignneoplasms exhibit slow, localized growth that is usually circumscribeddue to their encapsulation by a fibrous connective tissue capsule.Whereas benign neoplasms rarely cause the death of the organism,untreated malignant neoplasms have a high probability of killing theorganism. Malignant neoplasms are generally nonencapsulated, and usuallyexhibit a more rapid growth rate. Malignant neoplasms often invadesurrounding tissues and vessel and spread to distant body sites.Malignant neoplasms are generically described as “cancer” or as“tumors”; the latter term denotes swelling.

[0027] Myeloproliferative disorders are a group of disorderscharacterized by abnormal proliferation by one or more hematopoieticcell lines or connective tissue elements. Four disorders are normallyincluded as myeloproliferative disorders: polycythemia vera (primarypolycythemia; Vaquez' Disease), myelofibrosis (agnogenic myeloidmetaplasia), chronic myelogenous leukemia and primary (essential)thrombocythemia Acute leukemia, especially erythroleukemia, andparoxysmal nocternal hemoglobinuria are also classified asmyeloproliferative disorders. Each of these disorders is identifiedaccording to its predominant feature or site of proliferation. Althougheach results from proliferation of different cells, each has been shownto be caused by a clonal proliferation arising at the level of apluripotent stem cell, which causes varying degrees of abnormalproliferation of erythroid, myeloid, and megakaryocytic precursors inthe bone marrow. All myeloproliferative disorders have a tendency toterminate in acute leukemia.

[0028] Leukemias are malignant neoplasms of the blood-forming tissues.At least two viruses are associated with causing leukemias in humans.The Epstein-Barr virus is associated with Burkitt's lymphoma and thehuman T-cell lymphotropic virus, also called human acuteleukemia/lymphoma virus (HTLV-1) has been linked to some T cellleukemias and lymphomas. Exposure, especially prolonged exposure tochemical agents, such as benzene and some antineoplastics, or toionizing radiation, genetic predisposition (e.g. Down's syndrome) andsome familial disorders (e.g. Fanconi's anemia) result inpredispositions to leukemias.

[0029] Development of leukemias appears to occur through a single cellcycle through two or more steps with subsequent proliferation and clonalexpansion. Leukemias are currently classified according to theircellular maturity; acute leukemias are predominantly undifferentiatedcell populations and chronic leukemias are more mature cell forms. Acuteleukemias are further divided into lymphoblastic (ALL, also known asacute lymphocytic leukemia) and myeloid (AML, also known as acutemyelocytic, myelogenous, myeloblastic, myelomonoblastic) types. They maybe further classified by morphologic and cytochemical appearanceaccording to the French-American-British (FAB) classification oraccording to type and degree of differentiation. Chronic leukemias areclassified as either lymphocytic (CLL) or myelocytic (CML). CLL ischaracterized by the appearance of mature lymphocytes in the blood, bonemarrow and lymphoid organs. CML is characterized by the predominance ofgranulocytic cells of all stages of differentiation in blood, bonemarrow, liver, spleen and other organs.

[0030] Myelodysplastic Syndrome (MDS) is characterized as a clonalproliferative disorder in which a normal or hypercellular bone marrow isassociated with anemia and dysmyelopoiesis. Hemapoietic cells which mayproliferate include erythroid, myeloid and megakaryocytic forms. MDS isa relatively new designation of group of disorders known as Preleukemia,Refractory Anemias, Ph-Chromosome-Negative Chronic Myelocytic Leukemia,Chronic Myelomonocytic Leukemia and Agnogenic Myeloid Metaplasia The FABsystem provides further classification of Myelofibrosis.

[0031] Lymphomas are a heterogeneous group of neoplasms arising in thereticuloendothelial and lymphatic systems. The major types of lymphomasare Hodgkin's disease and non-Hodgkin's lymphoma, as well as the rarerBurkitt's lymphoma and mycosis fungoides. Hodgkin's disease is a chronicdisease with lymphoreticular proliferation of unknown cause that maypresent in localized or disseminated form, and is further classifiedaccording to four histopathologic profiles. Non-Hodgkin's lymphomas area heterogeneous group of diseases consisting of neoplastic proliferationof lymphoid cells that usually disseminate throughout the body. Theformer terms, lymphosarcoma and reticulum cell sarcoma, are now beingreplaced with terms that reflect that cell of origin and biology of thedisease. The Rappaport classification is based on the histopathology; onthe degree of the differentiation of the tumor; and on whether thegrowth pattern is diffuse or nodular. The Lukes and Collinsclassification is based upon the cell of origin, specifically whether itis T cell or B cell derived, histiocytic (or monocytic) origin orunclassifiable. The International Panel Working Formulation of theNational Cancer Institute categorizes non-Hodgkin's lymphomas using theabove classifications.

[0032] Burkitt's lymphoma is a highly undifferentiated B cell lymphomathat tends to involve sites other than the lymph nodes andreticulendoethlial system. Burkitt's lymphoma, unlike other lymphomas,has a specific geographic distribution, which suggests an unidentifiedinsect vector and an infectious agent. Evidence points to the herpeslike Epstein-Barr virus.

[0033] Mycosis fungoides is an uncommon chronic T cell lymphomaprimarily affecting the skin and occasionally internal organs.

[0034] Plasma cell dyscrasias (PCDs), or monoclonal gammopathy, aredisorders characterized by the disproportionate proliferation of oneclone of cells normally engaged in immunoglobulin (Ig) synthesis, andthe presence of a structurally and electrophoretically homogeneous IG orpolypeptide subunit in serum or urine. The disorders may be primarilyasymptomatic to progressive, overt neoplasms (e.g., multiple myeloma).The disorder results from disproportionate proliferation of one cloneproducing a specific Ig: IgG, IgM, IgA, IgD or IgE.

[0035] Multiple myeloma, also known as plasma cell myeloma ormyelomatosis, is a progressive neoplastic disease characterized bymarrow plasma cell tumors and overproduction of an intact monoclonal Ig(IgG, IgA, IgD or IgE) or Bence Jones protein, which is free monoclonalκ or λ light chains. Diffuse osteoporosis or discrete osteolytic lesionsarise due to replacement by expanding plasma cell tumors or aosteoclast-activating factor secreted by malignant plasma cells.

[0036] Macroglobulinemia, or primary or Waldenstrom's macroglobulinemia,is a plasma cell dyscrasia involving B cells that normally synthesizeand secrete IgM. Macrogolbulinemia is distinct from myeloma and otherPCDs, and resembles a lymphomatous disease. Many patients have symptomsof hyperviscosity, fatigue, weakness, skin and mucosal bleeding and soforth.

[0037] Heavy chain diseases are neoplastic plasma cell dyscrasiascharacterized by the overproduction of homogenous γ, α, μ, and δ Igheavy chains. These disorders result in incomplete monoclonal Igs. Theclinical picture is more like lymphoma than multiple myeloma.

[0038] Hypersplenism is a syndrome in which circulating cytopenia isassociated with splenomegaly. Treatment of patients with hypersplenismrequires therapy for the underlying disease, not splenectomy.Lymphoproliferative and myeloproliferative diseases are some, but notthe sole, causes of hypersplenism. Myeloproliferative disorders causinghypersplenism include polycythemia vera, myelofibrosis with myeloidmetaplasia, chronic myelogenous leukemia and essential thrombocythemiaChronic lymphocytic leukemia and the lymphomas (including Hodgkin'sdisease) are specific lymphoproliferative disorders that may causehypersplenism.

[0039] Lung tissue is the site for both benign and malignant primarytumors, as well as the site of metastasis from cancers of many otherorgans and tissues. Cigarette smoking causes an overwhelming percentageof lung cancers, estimated at over ninety percent of the cases in menand about seventy percent of the cases in women. Exposure tooccupational agents such as asbestos, radiation, arsenic, chromates,nickel, chloromethyl ethers, poison gas, and coke oven emissions is alsoassociated with lung cancer. The most common types of lung cancer aresquamous cell, small and large cell and adenocarcinoma.

[0040] About ninety-five percent of the stomach cancers are carcinoma;less common are lymphomas and leiomyosarcomas. Gastric carcinomas areclassified according to gross appearance; protruding, penetrating (thetumor has a sharp, well-circumscribed border and may be ulcerated) andspreading or miscellaneous, which has characteristics of two of theother types.

[0041] Pancreatic cancers may be exocrine tumors, which are mostlyadenocarcinomas arising from duct cells rather than the acinar cells, orendocrine tumors, which include insulinoama. Gastrin-producingpancreatic tumors involving cells of the non-β-type or in the duodenalwall can cause Zollinger-Ellison Syndrome, a syndrome marked byhypergastrinemeia Sometimes other endocrine abnormalities, particularlywith the parathyroids, or pituitary and adrenal glands cause apolyglandular disorder known as multiple endocring neoplasia (MEN).Non-β islet cell tumors may cause a syndrome known as Vipoma Syndrome,which is characterized by prolonged massive watery diarrhea.

[0042] Neoplasms of the bowel include tumors of the small intestine,tumors of the large intestine, and cancer of the colon and rectum.Benign small intestine tumors may arise from jejunal and ilealneoplasms, including leiomyomas, lipomas, neurofibromas, and fibromas.Malignant small intestine tumors, such as adenocarcinomas, are uncommon,and typically arise in the proximal jejunum. Patients with Crohn'sdisease of the small intestine are more prone to such adenocarcinomasrather than patients with Crohn's disease of the colon. In patients withCrohn's disease, the tumors tend to occur distally in the bypassed orinflamed loops of the bowel. Carcinoid tumors typically arise in thesmall bowel, especially the ileum, and in about half the cases, multipletumors exist. Kaposi's sarcoma, which occurs frequently in transplantrecipients and AIDS patients, have gastrointestinal involvement in abouthalf the cases. Lesions may occur anywhere in the GI tract, but areusually found in the stomach, small intestine, or distal colon.

[0043] Tumors of the large bowel include polyps of the colon and rectum.Polyps are a mass of tissue that arises from the bowel wall andprotrudes into the lumen. Polyps are classified on the basis of theirhistology, as tubular adenomas, tubulovillous adenomas, villousadenomas, hyperplastic polyps, hamartomas, juvenile polyps, polypoidcarcinomas, pseudopolyps, lipomas, leiomyomas and even rarer tumors.

[0044] Malignant tumors may also arise in the anorectum. These areepidermoid (squamous cells) carcinoma of the anorectum which compriseabout three to five percent of rectal and anal cancers.

[0045] In Western countries, cancer of the colon and rectum are secondto lung cancer in accounting for more new cases each year. In the USA,aobut 75,000 people died of these cancers in 1989; about 70% occurred inthe rectum and sigmoid colon, and 95% were adenocarcinomas.

[0046] Neoplasms of the liver include benign neoplasms, which arerelatively common but often undetected, and malignant neoplasms.Hepatocellular adenoma is the most important benign liver neoplasm.Asymptomatic small hemangiomas occur in one to five percent of adults.Bile duct adenomas and other mesenchymal neoplasms also occur, but arerelatively rare. Malignant neoplasms of the liver are the most commonform of hepatic tumor, and the liver is a frequent site of bloodbornemetastases, usually from lung, breast, colon, pancreas and stomachprimary tumors. The incidence of hepatocellular carcinoma is linked withchronic hepatitis B virus in certain parts of Africa and Southeast Asia.In North America, Europe and other areas of low prevelence, most of thepatients have underlying cirrhosis. Fibrolamellar carcinoma is a distantvariant of hepatocellular carcinoma with characteristic morphology ofmalignant hepatocytes enmeshed in lamellar fibrous tissue. Fibrolamellarcarcinoma usually affects relatively young adults, and has noassociation with preexisting cirrhosis, chronic hepatitis B virusinfection or other known risk factors. Other primary malignancies of theliver include cholangiocarcinoma (a tumor arising from intrahepaticbiliary epithelium), hepatoblastoma (which is one of the most commoncancers in infants) and angiosarcoma (which is associated withindustrial exposure to vinyl chloride). Leukemia and related disordersmay involve hepatic tissues, thought to be the result of infiltrationwith abnormal cells.

[0047] Multiple Endocrine Neoplasia (MEN) Syndromes are a group ofgenetically distinct familial diseases involving adenomatous hyperplasiaand malignant tumor formation in several endocrine glands. Threedistinct syndromes have been identified. Type I (MEN-I) is characterizedby tumors of the parathyroid glands, pancreatic islets, and thepituitary. Type II (MEN-II) is characterized by medullary carcinoma ofthe thyroid, pheochromocytoma and hperparthyroidism. Type III (MEN-III)is characterized by multiple mucosal neuromas, medullary carcinoma ofthe thyroid, and pheochromocytoma.

[0048] Carcinoid syndrome is usually caused by metastatic intestinalcarcinoid tumors that secrete excessive amount of vasoactive substances,including serotonin, bradykinin, histamine, prostaglandins andpolypeptide hormones. Abnormal levels of these subtances cause a varietyof symptoms, often episodic cutanteous flushing, cyanosis, abdominalcramps, diarrhea, and valvular heart disease.

[0049] Neoplasms of the bone and joints may be benign or malignant.Benign tumors of the bone include osteochondromas (osteocartilaginousexostoses), which are the most common benign bone tumors in childrenbetween ages 10 to 20, benign chondromas (which are located within thebone), which occur most commonly in children and young adults betweenthe ages 10 to 30, chondroblastoma (which arises in an epiphysis), whichis rare, but most common in children between the ages of 10 to 20,chondromyxofibromas, osteoid osteoma, giant cell tumors and fibromatouslesions. Primary malignant tumors of the bone include osteogenic sarcoma(osteosarcoma), which is the second most common primary bone tumor,fibrosarcomas, malignant fibrous histiocytoma, chondrosarcomas,mesenchymal chondrosarcoma, Ewing's tumor (Ewing's sarcoma), malignantlymphoma of bone, multiple myeloma, and malignant giant cell tumor.

[0050] Primary cancers of other tissues may metastasize to bone tissue.The most common are carcinomas arising in the breast, lung, prostate,kidney, and thyroid.

[0051] Central nervous system (CNS) neoplasms are generally classifiedaccording to the organ. Primary intracranial neoplasms are subdividedinto six classes: tumors of (1) the skull; (2) the meninges; (3) thecranial nerves; (4) the neuroglia and ependyma; (5) pituitary or pinealgland; and (6) those of congenital origin. Skull neoplasms includeosteoma, hemangioma, granuloma, xanthoma, and osteitis deformans. Themeninges neoplasms include meningioma, sarcoma, and glomatosis. Thecranial nerve neoplasms include glioma of the optic nerve, andschwannoma of the 8th and 5th cranial nerves. The neuroglia neoplasmsinclude gliomas and ependymomas. The pituitary or pineal body neoplasmsinclude pituitary adenoma and pinealoma. The congenital origin neoplamsinclude craniopharyngioma, chordoma, germinoma, teratoma, dermoid cyst,agioma and hemangioblastoma.

[0052] Spinal cord neoplasms are lesions that compress the spinal cordor its roots, arising from the cord parenchyma, roots, meninges, orvertebrae. Primary spinal cord neoplasms are much less common thanintracranial tumors. Metastatic lesions are common and may arise fromcarcinomas of the lung, breast, prostate, kidney, thyroid or lymphoma.

[0053] Genitourinary neoplasms occur at any age and in both sexes;however, they account for about 30% of cancer in the male and 4% in thefemale. Adenocarcinoma of the prostate accounts for a significant numberof malignancies in men over 50. Prostate adenocarcinoma is thought to behormone related and its pathology is typically glandular. Carcinoma ofthe kidney, adenocarcinoma, is only about one to two percent of adultcancers, but most solid kidney tumors are malignant. Wilms' tumors, anembryonal adenomyosarcoma of the kidneys, occurs fetally and is oftennot diagnosed for several years. Renal pelvis and ureter neoplasms arehistologically similar. Urinary bladder neoplasms may be induced byknown urinary carcinogens such as aniline dyes, and the most common istransitional cell carcinoma, less common is squamous cell carcinoma.Rarer genitourinary neoplasms include carcinoma of the urethra, andpenis. Neoplasms of the testis account for the majority of solidmalignancies in males under 30. Most malignant testicular tumors arisefrom the primordial germ cell and are classified according to the celltype involved.

[0054] Breast cancer is the most common cancer in women. In the USA, thecumulative risk for women of all ages of developing breast cancer isabout 10%, but that of dying from the disease is only about 3.6%.However, the risk increases with age, a family history of breast cancer,exposure to radiation, and even diet is implicated in higher risk.

[0055] Breast cancers are routinely typed for estrogen- andprogesterone-receptor analysis. About two thirds of the patients haveestrogen-receptor positive (ER+) breast tumors. Tumors which areprogesterone positive are thought to have functional estrogen receptorand the presence of both receptors gives a greater likelihood offavorable response to endocrine treatment than the presence of just onereceptor. Endocrine therapy, usually tamoxifen, is preferred in estrogenreceptor-positive tumors. Estrogens and androgens are also effective,but less favored due to undesirable side effects induced by higherlevels of these hormones than other forms of endocrine treatment. Breastcancer may metastasize to almost any organ in the body, but most commonsites of metastatisis are the lung, liver, bone, lymph nodes and skin.

[0056] Lobular carcinoma in situ (LCIS) or lobular neoplasia, is mostfrequently found in premenopausal women. Ductal carcinoma in situ (DCIS)occurs in both pre- and postmenopausal women. DCIS forms a palpablemass. LCIS and DCIS account for about 90% of all breast cancers. Therarer forms, medullary and tubular lesions, have a somewhat betterprognosis.

[0057] The most common gynecologic neoplasms are endometrial carcinomas,which ranks fourth in frequency after breast, colorectal and lungcancers in women. Endometrial carcinomas are characterized by theirclinical staging, ranging from in situ at stage 0, to metastasis todistant organs at stage IVB. Endometrial carcinomas typically produceestrogen and the current treatment approaches are surgery andprogesterone therapy.

[0058] Ovarian cancers account for about 18% of all gynecologicneoplasms. About 80% of malignant ovarian cancers arise from the ovarianepithelium and are classified according to their histology. Tumors mayalso arise from germ cells or stroma.

[0059] Vulvar carcinoma accounts for about 34% of all gynecologicneoplasms. Vulvar carcinoma usually occurs after menopause, and about90% are squamous cell carcinomas. About 4% are basal cell carcinomas andthe rest include intraepithelial carcinomas, adnocarcinoma ofBartholin's gland, fibrosarcoma and melanoma.

[0060] Vaginal carinoma accounts for about 1% of gynecologicmalignancies, with a peak incidence from about ages 45 to 65. About 95%of vaginal carcinomas are squamous cell carcinoma Primary carcinoma ofthe oviduct is rare, and typically spread directly or by the lymphatics.

[0061] Trophoblastic disease or neoplams of trophoblastic origin, canfollow intra- or extrauterine pregnancy. A degenerating pregancy resultsin a hydatidiform mole of which about 80% are benign.

[0062] Neoplasms may arise in the ear canal and affect hearing.Ceruminomas also arise, are typically malignant despite appearing benignhistologically and are treated by surgical removal. Basal cell andsquamous cell carcinomas frequently develop on the external ear as theresult from regular sun exposure, and are also typically treated bysurgical removal. The middle ear may be the site of squamous cellcarcinomas. Nonchromaffin paragangliomas may arise in the temporal bone.

[0063] The most common malignant tumor in the nose and paranasal sinusesis squamous cell carcinoma; less common are adenoid cystic andmucoepidermod carcinomas, malignant mixed tumors, adenocarcinomas,lymphomas, fibrosarcomas, osteosarcomas, chondrosarcomas, and melanomas.

[0064] Squamous cell carcinoma of the nasopharynx is more commonlyobserved in children and young adults.

[0065] The most common malignancies of the upper respiratory tract aresquamous cell carcinomas of the tonsil and of the larynx. Both are morecommon in males and are associated with tobacco smoking and ethanolingestion; about 85% of patients with cancer of the head or neck have ahistory of ethanol and tobacco consumption.

[0066] In the head and neck, about 90% of the cancers are squamous cell(epidermoid) carcinoma Melanomas, lymphomas and sarcomas are relativelyrare forms of primary head and neck cancers. Cancers of the head andneck are classified according to the size and site of involvement of theprimary neoplasm; number and size of metastases to the cervical lymphnodes; and evidence of distant metastases.

[0067] Ophthalmologic cancers may arise in the skin of the eyelids andmay be benign or neoplastic. Common benign growths are xanthelasmas,which form yellow-white flat plaques of lipid material subcutaneously.Basal cell carcinomas are more common; treatment is typically surgicalremoval or radiation therapy. Other less common malignant tumors aresquamous cell or meibomian gland carcinomas and other types ofmelanomas. The most common primary ocular malignancy is malignantmelanoma of the choroid.

[0068] Tumors also arise in the skin tissue, and include benign tumorssuch as moles, lipomas and the like, as well as malignant tumors. About40-50% of malignant melanomas arise from melanocytes in moles. Malignantskin cancers are either basal cell or squamous cell carcinomas andfrequently arise in sun-exposed areas of skin. They are the most commonmalignancies, and the incidence is rising. Less common malignanciesinclude malignant melanoma, Paget's disease of the nipple orestramammary Patent's, Kaposi's sarcoma (KS), and cutaneous T celllymphoma (mycosis fungiodes). The incidence of KS is increasing as theresult of the increased incidence of AIDS. KS arises in about one thirdof patients with AIDS.

[0069] Oral cancers account for about 5% of cancers in men and 2% ofcancers in women. The most common form of oral cancer is squamous cellcarcinoma. Incidence increases with age and risk factors, particularlytobacco and alcohol consumption.

[0070] Surgery is the oldest effective form of treatment of neoplasms.Success is largely achieved if the neoplasm is detected in its earlystages and has not metastasized. Radiation is also important therapy,and is the favored therapy of many neoplasms such as Hodgkin's disease,early stage non-Hodgkin's lymphomas, and squamous cell carcinoma of thehead and neck. Radiation has proven very successful as an adjunct tosurgery and antineoplastic drugs.

[0071] Antineoplastic drugs are also usefull in the treatment ofneoplasms, and are classified according to their mechanism of action.Numerous combinations, typically of antineoplastic drugs with differingmechanisms of action, have proven to be particularly effective therapy,permit lower doses and frequently minimize negative side effects.Antineoplastic drugs frequently target fundamental biological processesnecessary for cell replication or growth.

[0072] Alkylating agents, such as mechlorethamin and cyclophosphamide,alkylate DNA, and restrict DNA replication.

[0073] Antimetabolites, which are directed to disruption of necessarycell division pathways, include:

[0074] Folate antagonists bind to dehydrofolate reductase and interferewith pyrimidine synthesis. Folate antagonists are S-phase specific.Methotrexate is a very commonly used antineoplastic folate antagonist.

[0075] Purine antagonists block de novo purine synthesis and are S-phasespecific. 6-Mercaptopurine is an example of a purine antagonist.

[0076] Pyrimidine antagonists interfere with thymidylate synthase toreduce thymidine production and are S-phase specific. A frequently usedpyrimidine antagonist is 5-fluorouracil.

[0077] Cytarabine inhibits DNA polymerase and is S-phase specific.

[0078] Plant alkyloids include vincas, such as vinblastine andvincristine, and podophyllotoxins, such as etoposide. Plant alkyloidsare effective in the metaphase and inhibit mitosis by a variety ofmechanisms including altering microtubular proteins.

[0079] Antibiotics include doxorubicin and daunomycin, which intercalatebetween DNA strands to inhibit the uncoiling of DNA; bleomycin, whichcauses incisions in DNA strands; and mitomycin, which inhibits DNAsynthesis by acting as a bifunctional alkylator.

[0080] Nitrosureas include carmustine and lomustine and alkylate DNA orcause carbamoylate amino acids in proteins.

[0081] Inorganic ions, such as cisplatin, cause inter- and intracalationof DNA strands to inhibit the uncoiling of DNA.

[0082] Biologic Response Modifiers, such as the interferons, haveantiproliferative effects, but their specific role is not known.Interferons include a (leukocyte) interferon, β (fibroblast) interferonand γ (lymphocyte) interferon.

[0083] Enzymes, such as asparaginase, are also used to alter metabolicpathways important in cancerous cells. Asparaginase depletes the cell ofasparagine, on which leukemic cells depend.

[0084] Hormones and their analogs, such as tamoxifen, flutamide andprogesterone, have non-specific effects but are useful to treat certainneoplams which are known to be hormone responsive, especially breast,ovarian and prostate neoplasms. Tamoxifen, frequently used in thetreatment of breast neoplasms, places cells at rest, and binds to theestrogen receptor. Flutamide, frequently used in the treatment ofprostate neoplasms, binds the androgen receptor.

[0085] Cytokinins are naturally occurring and artificial plant growthregulators. Natural cytokinins tend to be non-specific inhibitors ofvarious protein kinases. The molecular mechanisms by which cytokininsregulate cell growth and division are still being determined. Studieshave indicated that cytokinins may increase accessibility of the DNAtemplate, activate RNA polymerases, affect polyadenylation and secondarystructure of mRNA and stimulate formation and activity of polyribosomes.Cytokinins are thought to affect cell division by interacting withregulatory proteins of the cell cycle. Both cytokinins andcyclin-dependent kinases (cdks) act at multiple and similar controlpoints of cell cycle, for example, at the G₁/S and G₂/M transitions andS and M phases.

[0086] Olomoucine,6-(benzylamino)-2-[(2-hydroxyethyl)amino]-9-methylpurine, was firstdiscovered as an herbicide. More recently, it has been discovered thatOlomoucine is an artificial cytokinin, which specifically inhibit somecdks, including p34^(cdc2)/cyclin B kinases, at micromolarconcentration, but has no effect on other major protein kinases such ascAMP- and cGMP-dependent kinases, and protein kinase C. Olomoucine hasrecently been shown to have good selectivity for the CDK-cyclin proteinkinases, but only has moderate inhibitory activity, with an IC₅₀ ofabout 7 μM. Vesely, J., el al., Eur. J. Biochem., 1994, 224, 771-786. A2.4 A crystal structure of olomucine co-crystallized with cdk2 revealedthat the purine portion of olomoucine binds in the conserved ATP bindingpocket, while the benzylamino group extends into a region of the activesite unique to the cdk2 kinases.

[0087] Roscovitine,2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine, is arecently synthesized purine which has been shown to have selectivitytowards some cyclin-dependent kinases and to be 10-fold more active oncdk2 and cdc2 than olomoucine (Meijer, L., et al., Eur. J. Biochem.,243:527-536, 1997 and PCT/FR96/01905). Meijer et al report that mostkinases are not significantly inhibited by roscovitine. However, cdc2-cyclin B, cdk 2-cyclin A, cdk 2-cyclin E and cdk 5-p35 aresubstantially inhibited with IC₅₀ values of 0.65, 0.7, 0.7 and 0.2 μM,respectively. In contrast, roscovitine displayed IC₅₀ values of greaterthan 100 μM for cdk 4-cyclin D1 and cdk 6-cyclin D2.

[0088] Havlicek, L., et al., J. Med. Chem. (1997)40:408-412 report thatRoscovitine, and related analogs substituted in the 2, 6 and/or 9positions, inhibit p34^(cdc2)-cyclin B kinases. None of the analogs hadsuperior IC₅₀ values over the (R) enantiomer of Roscovitine, which hadan IC₅₀ value of 0.2 μM. The (S) enantiomer had an IC₅₀ value of 0.8 μM;the racemic mixture (R/S) had an IC₅₀ value of 0.65 μM. These authorsconclude that the N⁶-benzyl substituent of Roscovitine was superior overthe isopentenyl or cyclohexylmethyl substituents.

[0089] The National Cancer Institute (NCI) is a US Government-runorganization directed at the discovery and development of noveltherapeutic oncology products. In 1985, the NCI established a new cancerscreening strategy involving human tumor cell lines in an in vitro assayas the primary cancer screen. A total of sixty human tumor cell lines,derived from seven cancer types (lung, colon, melanoma, renal, ovarian,brain and leukemia) were selected for inclusion in the NCI panel(Grever, M. R., et al., Seminars in Oncology, 19:1992:622-638). Theprotocols used in the assays have also been reported in the literature.American Type Tissue Collection (ATCC) acts as a depository for theseand other tumor cell lines. Useful human tumor cell lines include thefollowing:

[0090] MCF7: human breast adenocarcinoma, hormone-dependent;

[0091] MDA-MB-231: human breast adenocarcinoma, hormone-independent;

[0092] HT-29: human colon adenocarcinoma, moderately well-differentiatedgrade II;

[0093] HCT-15: human colon adenocarcinoma;

[0094] A549: human non-small cell lung carcinoma;

[0095] DMS-114: human small cell lung carcinoma;

[0096] PC-3: human prostate adenocarcinoma, hormone-independent; and

[0097] DU 145: human prostate carcinoma, hormone-independent.

[0098] Skehan, P., et al., J. Natl. Cancer Inst. 82: 1107-1112, 1990sets forth useful protocols for using such tumor cell lines forscreening antineoplastic drugs.

[0099] Meijer, et al., supra, report that roscovitine inhibits theproliferation of the NCI disease-oriented in vitro screen, i.e., 60human tumour cell lines comprising nine tumour types (leukemia,non-small cell lung cancer, colon cancer, central nervous system cancer,melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer)with an average IC₅₀ value of 16 μM. The results of individual tumourlines were not reported.

[0100] Two distinct cdk inhibitors, flavopiridol and olomoucine,suppress the death of neuronal PC12 cells and sympathetic neurons in twomodel systems of neuronal survival (Park et al., J. Biol. Chem.271(14):8161-8169, 1996). The concentration of each required to promotesurvival correlated with the amount required to inhibit proliferation.Neuronal apoptosis is an important aspect of both nervous systemdevelopment and a component of neuronal injury and disease.

[0101] The PC12 cell line was initially derived from a rat adrenalmedullary pheochromocytoma. When grown in serum-containing medium, PC12cells divide and resemble precursors of adrenal chromaffin cells andsympathetic neurons. Upon addition of nerve growth factor (NGF), PC12cells attain the phenotypic properties of sympathetic neurons. Uponremoval of either serum or serum and NGF, both naive and neuronallydifferentiated PC12 cells undergo apoptosis, which is analogous to theresponse of sympathetic neurons.

[0102] The role of cell cycle regulation in apoptosis may bedemonstrated by withdrawal of NGF or serum which results inuncoordinated cell cycle progression and cell death from naive PC-12cells. Cdk inhibitors did not prevent the death of these proliferationcompetent naive PC-12 cells after removal of trophic supportPost-mitotic differentiated or sympathetic neurons are hypothesized toattempt inappropriate re-entry of the cell cycle following withdrawal ofNGF which results in cell death. However, exposure to flavopiridol orolomoucine which inhibit cdks prevented apoptosis in these cells.

[0103] Changes in the activity of cdks and cyclins are observed duringapoptosis of many different cell types. Camptothecin- or araC-inducedapoptosis of HL60 cells is associated with elevated cdc2 activity andcyclin E-associated kinase activity. Camptothecin-induced apoptosis ofRKO cells is associated with an increase in expression of cyclin D1.

[0104] Camptothecin causes apoptotic death of rat cerebral corticalneurons. Morris and Geller, J. Cell Biol. 134:757-770(1996).Camptothecin-treated nonproliferating neuronally differentiated PC12cells die within 6 days after treatment, and cultured rat sympatheticneurons die within 5 days after treatment, even in the presence of NGF.Park et al., J. Neurosci. 17(4):1256-1270(1997). However, administrationof either both, or individual olomoucine or flavopiridol, in thepresence or absence of camptothecin resulted in approximately 30% celldeath at day 6. Maximal protection of PC12 cells, or rat sympatheticneurons, from death was observed with 1 μM flavopiridol and 200 μMolomoucine, which are the minimum concentrations that fully inhibit DNAsynthesis by proliferating PC12 cells. Administration of iso-olomoucine,an inactive analog of olomoucine, failed to prevent the cell death ofcamptothecin-treated neuronal cells

[0105] Flavopindol and olomoucine were also shown to protect againstcamptothecin-induced cortical neuronal death. Park et al., J. Neurosci.17(4):1256-1270(1997). The IC₅₀ values of flavopiridol and olomoucinewere 0.1 μM and 100 μM, respectively. Administration of iso-olomoucinefailed to prevent the cell death of camptothecin-treated neuronal cells.

[0106] There are several implications of the above observations. It iswell recognized that patients treated with radiation or antineoplasticagents experience undesirable side effects, including developing newneoplasms or undesirable cellular apoptosis. For example, some patientstreated with high-dose araC for refractory leukemia develop a cerebellartoxicity syndrome, characterized by loss of Purkinje neurons. Winkelmanand Hinges, Ann Neurol. 14:520-527(1983) and Vogel and Horouipian,Cancer 71:1303-1308(1993). Patients treated with cis-platinum have beenreported to develop periperal neuropathies. Wallach, et al., J. Fla.Med. Assoc. 79:821-822(1992) and Mansfield and Castillo, AJNR Am. J.Neuroradiol. 15:1178-1180(1994). In view of these observations, eitherco-administration or sole administration of the present compounds in thetreatment of neoplasms would reduce or preclude cellular apoptosis, inparticular, neuronal damage caused by treatment with antineoplasticagents or radiation.

[0107] Cerebrovascular disease is the most common cause of neurologicdisability in Western countries. The major specific types ofcerebrovascular disease are cerebral insufficiency due to transientdisturbances of blood flow, infarction, hemmorrhage, and arteriovenousmalformation. Stroke generally denotes ischemic lesions. Undesirableneuronal apoptosis occurs in cerebrovascular disease. Treatment withinhibitors of cdks may be an approach to prevent neuronal injury anddegeneration in such cases.

SUMMARY OF THE INVENTION

[0108] The present invention provides novel compounds of the formula (I)

[0109] wherein R is selected from the group consisting of R2, R2NH—, orR3R4N—R5— wherein

[0110] R2 is selected from the group consisting of C₉-C₁₂ alkyl,

[0111]  wherein each R6 is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m)-phenyl, wherein m is an integer 0-8; x is an integer 1-8; n isan integer 0-8; Z is selected from the group consisting of phenyl,heterocycle, cycloalkyl, and naphthanlene; and M is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl,

[0112] wherein each R6′ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m′)-phenyl, wherein m′ is an integer 0-8; n′ is an integer 0-8;x′ is an integer 1-8; Q is hydrogen or C₁-C₄ alkyl; and Z′ is selectedfrom the group consisting of phenyl, heterocycle, cycloalkyl, andnapthalene; and

[0113]  wherein each C₉-C₁₂ alkyl or Z is optionally substituted with 1to 3 substituents, which may be the same or different, and which areselected from the group consisting of D, E,

[0114]  wherein each D is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; eachE is independently selected from the group consisting of Hal, OH, andC₁-C₈ alkyl; b is an integer 0-2; Z″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6″is independently selected from the group consisting of hydrogen, C₃-C₈cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m″)-phenyl, wherein m″ is an integer0-8; n″ is an integer 0-8; x″ is an integer 1-8; and M′ is selected fromthe group consisting of hydrogen, C₁-C₄ alkyl,

[0115] wherein each R6′″ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m′″)-phenyl, wherein m′″ is an integer 0-8; n′″ is an integer0-8; x′″ is an integer 1-8; Q′ is hydrogen or C₁-C₄ alkyl; and Z′″ isselected from the group consisting of phenyl, heterocycle, cycloalkyl,and napthalene,

[0116]  wherein the groups M′ and Z″ may be optionally substituted withthe groups D′, E′ or

[0117] wherein each R6″″ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is an integer0-8; Q″ is hydrogen, C₁-C₄ alkyl or phenyl; each D′ is independentlyselected from the group consisting of trifluoromethyl, trifluoromethoxy,and C₁-C₄ alkoxy; each E′ is independently selected from the groupconsisting of Hal, OH, and C₁-C₈ alkyl;

[0118] R3 and R4 are selected from the group consisting of hydrogen,C₁-C₄ alkyl and (CH₂)_(y)-phenyl, wherein y is an integer 0-8, with theproviso that R3 and R4 not both be hydrogen;

[0119] R5 is C₁-C₈ alkylene; and

[0120] R1 is selected from the group consisting of cyclopentyl,cyclopentenyl and isopropyl,

[0121] and the pharmaceutically acceptable salts, optical isomers, andhydrates thereof,

[0122] with the proviso that when R2 is the group

[0123]  wherein n is 1 or greater; R1 is isopropyl or cyclopentyl; R6 ishydrogen, C₁-C₄ alkyl, or (CH₂)_(m)-phenyl; and Z is phenyl,heterocycle, or cycloalkyl, that Z is substituted with 1 to 3substituents, which may be the same or different, and which are selectedfrom the group consisting of

[0124]  wherein D, b, R6″, x″, n″, M′, and Z″ are as previously defined.

[0125] In addition, the present invention provides a method ofinhibiting cell cycle progression. More specifically, the presentinvention provides a method of inhibiting cdk-2.

[0126] The present invention also provides a method of preventingapoptosis in neuronal cells. A particularly preferred method of thepresent invention is preventing apoptosis of neuronal cells induced byantineoplastic agents or resulting from cerebrovascular disease. Anotherpreferred embodiment of the present invention is the method ofpreventing apoptosis induced by oxygen depletion. A more preferredinvention provides a method of preventing apoptosis inducedcerebrovascular disease. Another preferred invention provides a methodof preventing apoptosis induced by stroke or infarction.

[0127] The present invention provides a method of inhibiting thedevelopment of neoplasms. The present invention provides a method fortreating a patient afflicted with a neoplastic disease state comprisingadministering a compound of the formula provided. It is preferred thatthe amount administered is a therapeutically effective amount of acompound of the formula. A preferred method of the present inventionadministers a single compound of the formula provided. Alternatively, apreferred method of the present invention administers an amount of acompound of the formula in conjunction with other antineoplastic agents.

[0128] In addition, the present invention provides a compositioncomprising an assayable amount of a compound of Formula (I) in admixtureor otherwise in association with an inert carrier. The present inventionalso provides a pharmaceutical composition comprising an effectiveinhibitory amount of a compound of Formula (I) in admixture or otherwisein association with one or more pharmaceutically acceptable carriers orexcipients.

DETAILED DESCRIPTION OF THE INVENTION

[0129] The present invention provides novel compounds of the formula (I)

[0130] wherein R is selected from the group consisting of R2, R2NH—, orR3R4N—R5— wherein

[0131] R2 is selected from the group consisting of C₉-C₁₂ alkyl,

[0132]  wherein each R6 is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m)-phenyl, wherein m is an integer 0-8; x is an integer 1-8; n isan integer 0-8; Z is selected from the group consisting of phenyl,heterocycle, cycloalkyl, and naphthanlene; and M is selected from thegroup consisting of hydrogen, C₁-C₄ alkyl,

[0133] wherein each R6′ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m′)-phenyl, wherein m′ is an integer 0-8; n′ is an integer 0-8;x′ is an integer 1-8; Q is hydrogen or C₁-C₄ alkyl; and Z′ is selectedfrom the group consisting of phenyl, heterocycle, cycloalkyl, andnapthalene; and

[0134]  wherein each C₉-C₁₂ alkyl or Z is optionally substituted with 1to 3 substituents, which may be the same or different, and which areselected from the group consisting of D, E,

[0135]  wherein each D is independently selected from the groupconsisting of trifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; eachE is independently selected from the group consisting of Hal, OH, andC₁-C₈ alkyl; b is an integer 0-2; Z″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthalene; each R6″is independently selected from the group consisting of hydrogen, C₃-C₈cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m″)-phenyl, wherein m″ is an integer0-8; n″ is an integer 0-8; x″ is an integer 1-8; and M′ is selected fromthe group consisting of hydrogen, C₁-C₄ alkyl,

[0136] wherein each R6′ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m′″)-phenyl, wherein m′″ is an integer 0-8; n′″ is an integer0-8; x′″ is an integer 1-8; Q′ is hydrogen or C₁-C₄ alkyl; and Z′″ isselected from the group consisting of phenyl, heterocycle, cycloalkyl,and napthalene,

[0137]  wherein the groups M′ and Z″ may be optionally substituted withthe groups D′, E′ or

[0138] wherein each R6″″ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m)″″-phenyl, wherein m″″ is an integer 0-8; x″″ is an integer0-8; Q″ is hydrogen, C₁-C₄ alkyl or phenyl; each D′ is independentlyselected from the group consisting of trifluoromethyl, trifluoromethoxy,and C₁-C₄ alkoxy; each E′ is independently selected from the groupconsisting of Hal, OH, and C₁-C₈ alkyl;

[0139] R3 and R4 are selected from the group consisting of hydrogen,C₁-C₄ alkyl and (CH₂)_(y)-phenyl, wherein y is an integer 0-8, with theproviso that R3 and R4 not both be hydrogen;

[0140] R5 is C₁-C₈ alkylene; and

[0141] R1 is selected from the group consisting of cyclopentyl,cyclopentenyl and isopropyl,

[0142] and the pharmaceutically acceptable salts, optical isomers, andhydrates thereof,

[0143] with the proviso that when R2 is the group

[0144]  wherein n is 1 or greater; R1 is isopropyl or cyclopentyl; R6 ishydrogen, C₁-C₄ alkyl, or (CH₂)_(m)-phenyl; and Z is phenyl,heterocycle, or cycloalkyl, that Z is substituted with 1 to 3substituents, which may be the same or different, and which are selectedfrom the group consisting of

[0145]  wherein D, b, R6″, x″, n″, M′, and Z″ are as previously defined.

[0146] As used herein, the term “heterocycle” means any closed-ringmoiety in which one or more of the atoms of the ring are an elementother than carbon and includes, but is not limited to the following:piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl,morpholinyl, piperazinyl, benzimidazolyl, thiazolyl, thiophene, furanyl,indolyl, 1,3-benzodioxolyl, tetrahydropyranyl, imidazolyl,tetrahydrothiophene, pyranyl, dioxanyl, pyrrolyl, pyrimidinyl,pyrazinyl, triazinyl, oxazolyl, purinyl, quinolinyl, and isoquinolinyl.

[0147] As used herein, the term “C₁-C₄ alkyl” refers to a saturated orunsaturated, straight of branched chain hydrocarbyl radical of from oneto four carbon atoms and includes, but is not limited to the following:methyl, ethyl, propyl, isopropyl, 1-propenyl, 2-propenyl, n-butyl,isobutyl, tertiary butyl, sec-butyl, 1-butenyl, 2-butenyl, 3-butenyl,and the like.

[0148] As used herein, the term “C₁-C₈ alkyl” refers to a saturated orunsaturated, straight or branched chain hydrocarbyl radical of from oneto eight carbon atoms and includes, but is not limited to the following:methyl, ethyl, propyl, isopropyl, 1-propenyl, 2-propenyl, n-butyl,isobutyl, tertiary butyl, sec-butyl, 1-butenyl, 2-butenyl, 3-butenyl,pentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0149] As used herein, the term “C₁-C₁₂ alkyl” refers to a saturated orunsaturated, straight or branched chain hydrocarbyl radical of from nineto twelve carbon atoms and includes, but is not limited to thefollowing: nonyl, decyl, undecyl, and dodecyl, and the like.

[0150] As used herein, the term “C₁-C₈ alkylene” refers to a saturatedor unsaturated, straight of branched chain hydrocarbylene radical offrom one to eight carbon atoms and includes, but is not limited to thefollowing: methylene, ethylene, propylene, isopropylene, 1-propenylene,2-propenylene, n-butylene, isobutylene, tertiary butylene, sec-butylene,1-butenylene, 2-butenylene, 3-butenylene, pentylene, neopentylene,hexylene, heptylene, octylene, and the like.

[0151] As used herein, the term “cycloalkyl” refers to a saturated orunsaturated alicyclic moiety containing three to eight carbon atoms andincludes, but is not limited to, the following: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0152] As used herein, the designation

[0153] refers to a sulfur atom which is optionally oxidized to asulfoxide (b=1) or a sulfone (b=2).

[0154] As used herein, the term “Hal” refers to a halogen moiety andincludes fluoro, chloro, bromo, and iodo moieties.

[0155] As used herein, the term “optical isomer” or “optical isomers”refers to any of the various stereo isomeric configurations which mayexists for a given compounds of Formula (I).

[0156] As used herein, the term “hydrate” or “hydrates” refers to thereaction product of one or more molecules of water with a compound offormula (I) in which the H—OH bond is not split and includesmonohydrates as well as multihydrates.

[0157] As used herein, the term “pharmaceutically acceptable salts”refers to the reaction product of one or more molecules of anynon-toxic, organic or inorganic acid with the compounds of Formula (I).Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophosphate and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includemono, di and tricarboxylic acids. Illustrative of such acids are, forexample, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonicacid, succinic acid, glutaric acid, fumaric acid, malic acid acid,tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleicacid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamicacid, salacylic acid, 2-phenoxybenzoic acid and sulfonic acids such asmethane sulfonic acid, trifluoromethane sulfonic acid and2-hydroxyethane sulfonic acid.

[0158] The compounds of Formula (I) can be prepared by utilizingprocedures and techniques well known and appreciated by one of ordinaryskill in the art. A general synthetic scheme for preparing thesecompounds is set forth in Scheme A wherein all substituents, unlessotherwise indicated, are as previously defined.

[0159] In Scheme A, step a, 2,6-dichloropurine (1) is reacted with theappropriate alcohol of structure 2 to give the corresponding9-substituted-2,6-dichloropurine compound of structure 3 usingtechniques and procedures well known to one of ordinary skill in theart.

[0160] For example, 2,6-dichloropurine (1) can be reacted with theappropriate alcohol of structure 2 in the presence of triphenylphosphineand diethyl azodicarboxylate in a suitable anhydrous aprotic solvent,such as tetrahydrofuran. The reactants are typically stirred together atroom temperature for a period of time ranging from 5 hours to 5 days.The resulting 9-substituted-2,6-dichloropurine of structure 3 may berecovered from the reaction zone by extractive methods as is known inthe art or more typically, the resulting9-substituted-2,6-dichloropurine of structure 3 is recovered by removalof solvent following by charging directly onto a silica gel column andeluting with a sutiable solvent, such as methylene chloride or mixtureof solvents, such as a mixture of hexane and ethyl acetate. The crude9-substituted-2,6-dichloropurine of structure 3 may then be purified bychromatography or may be used in the next step without purification.

[0161] In step b, the 6-chloro functionality of the9-substituted-2,6-dichloropurine of structure 3 is reacted with anappropriate amine of structure 4 to give the corresponding9-substituted-6-amino-2-chloropurine compound of structure 5.

[0162] For example, the 9-substituted-2,6-dichloropurine of structure 3can be reacted with the appropriate amine of structure 4 in a suitableanhydrous polar solvent such as ethanol. The reactants are typicallystirred together at reflux temperatures for a period of time rangingfrom 30 minutes to 3 days. The resulting9-substituted-6-amino-2-chloropurine of structure 5 is recovered fromthe reaction zone by extractive methods as are known in the art, or, ifthe 9-substituted-6-amino-2-chloropurine of structure 5 precipitates outof solution, it may be recovered by filtration.

[0163] In step c, the 2-chloro functionality of the9-substituted-6-amino-2-chloropurine of structure 5 is reacted with1,4-cyclohexanediamine (6) to give the corresponding compound of FormulaI.

[0164] For example, the appropriate 9-substituted-6-amino-2-chloropurineof structure 5 can be reacted with a molar excess of1,4-cyclohexanediamine (6). The reactants are typically placed in apressure tube, sealed, and heated at a temperature of from about 80° C.to about 150° C. for a period of time ranging from 30 minutes to 3 days.The resulting compound of Formula I is recovered from the reaction zoneby extractive methods as are known in the art and may be purified bychromatography.

[0165] Starting materials for use in the general synthetic proceduresoutlined in Scheme A are readily available to one of ordinary skill inthe art. For example, certain 4-aminopiperidines and 3-aminopyrrolidinesof structure 4 may be prepared as described in Schemes B and C below.

[0166] Starting amines of structure 4 for use in Scheme A which are4-amino-1-piperidine and 3-amino-1-pyrrolidine derivatives (structure4′) may be prepared as shown in Scheme B, wherein all substituents,unless otherwise indicated, are as previously defined.

[0167] In Scheme B, step a, the free amino functionality of anappropriate 4-carboxamide-1-piperidine or 3-carboxamide-1-pyrrolidinederivative of structure 7 is reacted with the appropriate alkyl halideof structure 8 to give the corresponding4-carboxamide-1-alkylated-piperidine or3-carboxamide-1-alkylated-pyrrolidine of structure 9.

[0168] For example, the 4-carboxamide-1-piperidine or3-carboxamide-1-pyrrolidine of structure 7 can be reacted with theappropriate alkyl halide of structure 8 in a suitable aprotic organicsolvent, such as 3-pentanone, in the presence of a suitable base, suchas cesium carbonate, and a catalytic amount of a suitable alkylationcatalyst, such as potassium iodide. The reactants are typically stirredtogether at reflux temperature for a period of time ranging from 30minutes to 12 hours. The resulting 4-carboxamide-1-alkylated-piperidineor 3-carboxamide-1-alkylated pyrrolidine of structure 9 is recoveredfrom the reaction zone by filtration and evaporation of solvent.

[0169] In step b, the carboxamide functionality of the appropriate4-carboxamide-1-alkylated piperidine or 3-carboxamide-1-alkylatedpyrrolidine of structure 9 is dehydrogenated to give the corresponding4-amino-1-alkylated-piperidine or 3-amino-1-alkylated-pyrrolidine ofstructure 4′.

[0170] For example, the appropriate 4-carboxamide-1-alkylated piperidineor 3-carboxamide-1-alkylated pyrrolidine of structure 9 is reacted witha molar excess of bis(trifluoroacetoxy)iodobenzene in a suitable aproticpolar solvent such as acetonitrile. The reactants are typically stirredtogether at a temperature of about 50° C. to about 95° C. for a periodof time ranging from 30 minutes to 5 hours. The resulting4-amino-1-alkylated-piperidine or 3-amino-1-alkylated-pyrrolidine ofstructure 4′ is recovered from the reaction zone by extractive methodsas are known in the art.

[0171] Alternatively, starting amines of structure 4 for use in Scheme Awhich are 4-amino-1-piperidine and 3-amino-1-pyrrolidine derivatives(structure 4′) may be prepared as shown in Scheme C, wherein allsubstituents, unless otherwise indicated, are as previously defined.

[0172] Scheme C, step a, the free amino functionality of an appropriate4-piperidone or 3-pyrrolidone derivative of structure 10 is reacted withthe appropriate alkyl halide of structure 8 to give the corresponding1-alkylated-4-piperidone or l-alkylated-3-pyrrolidone of structure 11.

[0173] For example, the 4piperidone or 3-pyrrolidone of structure 10 canbe reacted with the appropriate alkyl halide of structure 8 in asuitable aprotic organic solvent, such as 3-pentanone, in the presenceof a suitable base, such as cesium carbonate, and a catalytic amount ofa suitable alkylation catalyst, such as potassium iodide. The reactantsare typically stirred together at reflux temperature for a period oftime ranging from 30 minutes to 12 hours. The resulting1-alkylated-4-piperidone or 1-alkylated-3-pyrrolidone of structure 11 isrecovered from the reaction zone by filtration and evaporation ofsolvent.

[0174] In step b, the ketone functionality of the appropriate1-alkylated-4-piperidone or 1-alkylated-3-pyrrolidone of structure 11 isreacted with hydroxylamine hydrochloride (12) to give the corresponding1-alkylated-4-piperidone oxime or 1-alkylated-3-pyrrolidone oxime ofstructure 13.

[0175] For example, the 1-alkylated-4-piperidone or1-alkylated-3-pyrrolidone of structure 11 is reacted with hydroxylaminehydrochloride (12) in the presence of a suitable base, such as sodiumacetate in a suitable protic solvent, such as aqueous ethanol. Thereactants are typically stirred together at reflux temperatures for aperiod of time ranging from 30 minutes to 5 hours. The resulting1-alkylated-4-piperidone oxime or 1-alkylated-3-pyrrolidone oxime ofstructure 13 is recovered from the reaction zone by extractive methodsas are known in the art.

[0176] In step c, the oxime functionality of the appropriate1-alkylated-4-piperidone oxime or 1-alkylated-3-pyrrolidone oxime ofstructure 13 is reduced to give the correponding 4-amino-1-piperidineand 3-amino-1-pyrrolidine derivatives (structure 4′).

[0177] For example, the 1-alkylated-4-piperidone oxime or1-alkylated-3-pyrrolidone oxime of structure 13 is reacted with asuitable reducing agent, such as lithium aluminum hydride; in a suitableanhydrous solvent, such as tetrahydrofuran under an inert atmosphere.The reactants are typically stirred together at reflux temperature for aperiod of time ranging from 30 minutes to 5 hours. The resulting4-amino-1-piperidine and 3-amino-1-pyrrolidine derivatives (structure4′) is recovered from the reaction zone by extractive methods as areknown in the art.

[0178] The following examples present typical syntheses as described inScheme A. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Asused herein, the following terms have the indicated meanings: “g” refersto grams; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “° C.” refers to degrees Celsius; “mm Hg”refers to millimeters of mercury; “μL” refers to microliters; “μg”refers to micrograms; “μM” refers to micromolar, and “APCI” refers toAtmospheric Pressure Chemical Ionization. Rf values are determined by anAQ 4×50 column (YMC) with a linear gradient from 100% C to 100% D infour minutes with a two minute hold at 100% D, where C is 5:95acetonitrile:water with 0.1% TFA, and D is 95:5 acetonitrile:water with0.085% TFA. Molecular ion determinations were made using a Finnigan MATSSQ-7:10 mass spectrometer.

EXAMPLE 12-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0179] Scheme A, Step a: 2,6-Dichloro-9-cyclopentylpurine

[0180] Dissolve cyclopentanol (260 mg, 3.02 mmol), 2,6-dichloropurine(680 mg, 3.60 mmol) and triphenyl phosphine (950 mg, 3.60 mmol) in dryTHF (20 mL) and cool to 0° C. Add diethyl azodicarboxylate (570 μL, 3.60mmol) dropwise over a period of 15 minutes under a nitrogen atmosphere.Stir the resulting solution for 60 hours at room temperature. Evaporatethe solvent in vacuo, charge directly onto a silica gel column, andelute with methylene chloride to give the title compound as a crudemixture.

[0181] Scheme A, Step b:2-Chloro-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurine

[0182] Dissolve 2,6-dichloro-9-cyclopentylpurine (3.00 mmol),4-trifluorobenzylamine (3.00 mmol) and triethylamine (835 μL, 6.00 mmol)in dry ethanol (20 mL). Heat at reflux for 15 hours, cool, and filterthe solid to give the title compound.

[0183] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0184] Mix 2-chloro-6-[(4-trifluorobenzyl)amino]-9-cyclopentylpurine(0.287 mmol) and 1,4-cyclohexanediamine (2.00 g, excess) in a pressuretube, seal and heat to 140° C. for 18 hours. Cool the reaction mixture,add CH₂Cl₂ (40 mL) and wash with H₂O (2×20 mL). Dry (MgSO₄), evaporatethe solvent in vacuo, and purify by silica gel chromatography(10:1:drops CH₂Cl₂/MeOH/NH₄OH) to give the title compound. Convert tothe hydrochloride salt

[0185] CIMS (NH₃) 474 (MH⁺); Rf (min.)=0.58

EXAMPLE 22-[Trans-(4-aminocyclohexyl)amino]-6-(2-chlorophenylhydrazino)-9-cyclpentylpurineDihydrochloride

[0186] Scheme A, Step b:2-Chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurine

[0187] 2-Chloro-6-(2-chlorophenylhydrazino)-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 2-chlorophenylhydrazine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0188] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(2-chlorophenylhydrazino)-9-cyclopentylpurineDihydrochloride

[0189]2-[Trans-(4-aminocyclohexyl)amino]-6-(2-chlorophenylhydrazino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-(2-chlorophenylhydrazino)-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0190] CIMS (NH₃) 475 (MH⁺); Rf (min.)=3.49

EXAMPLE 32-[Trans-(4-aminocyclohexyl)amino]-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurineDihydrochloride

[0191] Scheme A, Step b:2-Chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine

[0192] 2-Chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,3,4,5-trimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0193] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurineDihydrochloride

[0194]2-[Trans-(4-aminocyclohexyl)amino]-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0195] CIMS (NH₃) 496 (MH⁺); Rf (min.)=3.42

EXAMPLE 42-[Trans-(4-aminocyclohexyl)amino]-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0196] Scheme A, Step b:2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine

[0197] 2-Chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2,6-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0198] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0199]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(2,6-dimethoxybenzyl)amino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0200] CIMS (NH₃) 466 (MH⁺); Rf (min.)=2.29

EXAMPLE 52-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurineDihydrochloride

[0201] Scheme A, Step b:2-Chloro-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurine

[0202] 2-Chloro-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-trifluoromethoxyaniline, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0203] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurineDihydrochloride

[0204]2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(4-trifluoromethoxy)phenylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0205] CIMS (NH₃) 476 (MH⁺); Rf (min.)=4.00

EXAMPLE 62-[Trans-(4-aminocyclohexyl)amino]-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurineTrihydrochloride

[0206] Scheme A, Step b:2-Chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurine

[0207] 2-Chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2-diethylaminoethylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0208] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurineTrihydrochloride

[0209]2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[2-(diethylamino)ethylamino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0210] CIMS (NH₃) 415 (MH⁺); Rf (min.)=3.15

EXAMPLE 72-[Trans-(4-aminocyclohexyl)amino]-6-[(1-napthyl)methylamino]-9-cyclopentylpurineDihydrochloride

[0211] Scheme A, Step b:2-Chloro-6-[(1-napthyl)methylamino]-9-cyclopentylpurine

[0212] 2-Chloro-6-[(1-napthyl)methylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,1-(aminomethyl)naphthylene, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0213] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-napthyl)methylamino]-9-cyclopentylpurineDihydrochloride

[0214]2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-napthyl)methylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(1-napthyl)methylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0215] CIMS (NH₃) 456 (MH⁺); Rf (min.)=3.43

EXAMPLE 82-[Trans-(4-aminocyclohexyl)amino]-6-[4-methoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0216] Scheme A, Step b:2-Chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine

[0217] 2-Chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-methoxybenzylamine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0218] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0219]2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(4-methoxybenzyl)amino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0220] CIMS (NH₃) 436 (MH⁺); Rf (min.)=2.28

EXAMPLE 92-[Trans-(4-aminocyclohexyl)amino]-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurineDihydrochloride

[0221] Scheme A, Step b:2-Chloro-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurine

[0222]2-Chloro-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 5-methoxytryptamine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0223] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurineDihydrochloride

[0224]2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(3-(5-methoxyindolyl))-2-ethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0225] CIMS (NH₃) 489 (MH⁺); Rf (min.)=3.44

EXAMPLE 102-[Trans-(4-aminocyclohexyl)amino]-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurineDihydrochloride

[0226] Scheme A, Step b:2-Chloro-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurine

[0227]2-Chloro-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-(aminomethyl)cyclohexanemethanol, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0228] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurineDihydrochloride

[0229]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[4-(hydroxymethyl)cyclohexanemethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0230] CIMS (NH₃) 442 (MH⁺); Rf (min.)=3.34

EXAMPLE 112-[Trans-(4-aminocyclohexyl)amino]-6-[2-fluorophenylhydrazino]-9-cyclopentylpurineDihydrochloride

[0231] Scheme A, Step b:2-Chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine

[0232] 2-Chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorophenylhydrazine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0233] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2-fluorophenylhydrazino]-9-cyclopentylpurineDihydrochloride

[0234]2-[Trans-(4-aminocyclohexyl)amino]-6-[2-fluorophenylhydrazino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0235] CIMS (NH₃) 425 (MH⁺); Rf (min.)=3.41

EXAMPLE 122-[Trans-(4-aminocyclohexyl)amino]-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0236] Scheme A, Step b:2-Chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine

[0237] 2-Chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 2-methoxybenzylamine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0238] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0239]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0240] CIMS (NH₃) 436 (MH⁺); Rf (min.)=2.30

EXAMPLE 132-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0241] Scheme A, Step b:2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine

[0242] 2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2,3-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0243] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0244]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0245] CIMS (NH₃) 466 (MH⁺); Rf (min.)=2.29

EXAMPLE 142-[Trans-(4-aminocyclohexyl)amino]-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurineDihydrochloride

[0246] Scheme A, Step b:2-Chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine

[0247] 2-Chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2-(4-methoxyphenyl)ethylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0248] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurineDihydrochloride

[0249]2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[2-(4-methoxyphenyl)ethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0250] CIMS (NH₃) 450 (MH⁺); Rf (min.)=3.53

EXAMPLE 152-[Trans-(4-aminocyclohexyl)amino]-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurineDihydrochloride

[0251] Scheme A, Step b:2-Chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurine

[0252] 2-Chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,3-(2-methoxyethoxy)propylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0253] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurineDihydrochloride

[0254]2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[3-(2-methoxyethoxy)propylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0255] CIMS (NH₃) 432 (MH⁺); Rf (min.)=3.31

EXAMPLE 162-[Trans-(4-aminocyclohexyl)amino]-6-(2-methoxyethylamino)-9-cyclopentylpurineDihydrochloride

[0256] Scheme A, Step b:2-Chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine

[0257] 2-Chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 2-methoxyethylamine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0258] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(2-methoxyethylamino)-9-cyclopentylpurineDihydrochloride

[0259]2-[Trans-(4-aminocyclohexyl)amino]-6-(2-methoxyethylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(2-methoxyethylamino)-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0260] CIMS (NH₃) 374 (MH⁺); Rf (min.)=3.23

EXAMPLE 172-[Trans-(4-aminocyclohexyl)amino]-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0261] Scheme A, Step b:2-Chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine

[0262] 2-Chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2,4-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0263] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0264]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(2,4-dimethoxybenzyl)amino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0265] CIMS (NH₃) 466 (MH⁺); Rf (min.)=2.29

EXAMPLE 182-[Trans-(4-aminocyclohexyl)amino]-6-[(3-diethylamino)propylamino]-9-cyclopentylpurineDihydrochloride

[0266] Scheme A, Step b:2-Chloro-6-[(3-diethylamino)propylamino]-9-cyclopentylpurine

[0267] 2-Chloro-6-[(3-diethylamino)propylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,3-diethylaminopropylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0268] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-diethylamino)propylamino]-9-cyclopentylpurineDihydrochloride

[0269]2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-diethylamino)propylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(3-diethylamino)propylamino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0270] CIMS (NH₃) 429 (MH⁺); Rf (min.)=3.13

EXAMPLE 192-[Trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0271] Scheme A, Step a: 2,6-Dichloro-9-(2-propyl)purine

[0272] 2,6Dichloro-9-(2-propyl)purine is prepared from2,6-dichloropurine and isopropanol essentially as described in Example1, Scheme A, step a, but substituting isopropanol for cyclopentanol.

[0273] Scheme A, Step b:2-Chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine

[0274] 2-Chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine isprepared from 2,6-dichloro-9-(2-propyl)purine, 3,4-dimethoxybenzylamine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0275] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0276]2-[Trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride is prepared from2-chloro-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purine essentiallyas described in Example 1, Scheme A, step c.

[0277] CIMS (NH₃) 440 (MH⁺) Rf (min.)=3.33

EXAMPLE 202-[Trans-(4-aminocyclohexyl)amino]-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurineDihydrochloride

[0278] Scheme A, Step b:2-Chloro-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine

[0279] 2-Chloro-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2,6-dichlorophenylhydrazine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0280] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurineDihydrochloride

[0281]2-[Trans-(4-aminocyclohexyl)amino]-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[2,6-dichlorophenylhydrazino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0282] CIMS (NH₃) 475 (MH⁺); Rf (min.)=3.43

EXAMPLE 212-[Trans-(4-aminocyclohexyl)amino]-6-(3-fluorophenylamino)-9-cyclopentylpurineDihydrochloride

[0283] Scheme A, Step b:2-Chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine

[0284] 2-Chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 3-fluoroaniline, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0285] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(3-fluorophenylamino)-9-cyclopentylpurineDihydrochloride

[0286]2-[Trans-(4-aminocyclohexyl)amino]-6-(3-fluorophenylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(3-fluorophenylamino)-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0287] CIMS (NH₃) 448 (MH⁺); Rf (min.)=3.44

EXAMPLE 222-[Trans-(4-aminocyclohexyl)amino]-6-(3-methoxypropylamino)-9-cyclopentylpurineDihydrochloride

[0288] Scheme A, Step b:2-Chloro-6-(3-methoxypropylamino)-9-cyclopentylpurine

[0289] 2-Chloro-6-(3-methoxypropylamino)-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 3-methoxypropylamine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0290] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(3-methoxypropylamino)-9-cyclopentylpurineDihydrochloride

[0291]2-[Trans-(4-aminocyclohexyl)amino]-6-(3-ethoxypropylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(3-methoxypropylamino)-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0292] CIMS (NH₃) 388 (MH⁺); Rf (min.)=3.29

EXAMPLE 232-[Trans-(4-aminocyclohexyl)amino]-6-[(4-pentyl)phenylamino]-9-cyclopentylpurineDihydrochloride

[0293] Scheme A, Step b:2-Chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine

[0294] 2-Chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 4-butylphenylamine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0295] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-pentyl)phenylamino]-9-cyclopentylpurineDihydrochloride

[0296]2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-pentyl)phenylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0297] CIMS (NH₃) 462 (MH⁺); Rf (min.)=4.15

EXAMPLE 24(+/−)-2-[Trans-(4-aminocyclohexyl)amino]-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0298] Scheme A, Step b:2-Chloro-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine

[0299]2-Chloro-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,α-cyclopropyl-4-chlorobenzylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0300] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0301]2-[Trans-(4-aminocyclohexyl)amino]-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0302] CIMS (NH₃) 480 (MH⁺); (min.)=2.35

EXAMPLE 252-[Trans-(4-aminocyclohexyl)amino]-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0303] Scheme A, Step b:2-Chloro-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurine

[0304] 2-Chloro-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, 2-trifluorobenzylamine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0305] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0306]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(2-trifluorobenzyl)amino]-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0307] CIMS (NH₃) 474 (MH⁺); Rf (min.)=2.31

EXAMPLE 262-[Trans-(4-aminocyclohexyl)amino]-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurineDihydrochloride

[0308] Scheme A, Step b:2-Chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine

[0309] 2-Chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2-(2-aminoethoxy)ethanol, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0310] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurineDihydrochloride

[0311]2-[Trans-(4-aminocyclohexyl)amino]-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(2-hydroxyethoxyethylamino)-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0312] CIMS (NH₃) 404 (MH⁺); Rf (min.)=3.16

EXAMPLE 272-[Trans-(4-aminocyclohexyl)amino]-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurineDihydrochloride

[0313] Scheme A, Step b:2-Chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine

[0314] 2-Chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2-(3-methoxyphenyl)ethylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0315] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurineDihydrochloride

[0316]2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[2-(3-methoxyphenyl)ethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0317] CIMS (NH₃) 450 (MH⁺); Rf (min.)=3.54

EXAMPLE 282-[Trans-(4-aminocyclohexyl)amino]-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0318] Scheme A, Step b:2-Chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine

[0319] 2-Chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,3,5-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0320] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0321]2-[Trans-(4-aminocyclohexyl)amino]-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0322] CIMS (NH₃) 466 (MH⁺); Rf (min.)=2.27

EXAMPLE 292-[Trans-(4-aminocyclohexyl)amino]-6-(4-methoxybutylamino)-9-cyclopentylpurineDihydrochloride

[0323] Scheme A, Step b:2-Chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine

[0324] 2-Chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine is preparedfrom 2,6-dichloro-9-cyclopentylpurine, 4-methoxybutylamine andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0325] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(4-methoxybutylamino)-9-cyclopentylpurineDihydrochloride

[0326]2-[Trans-(4-aminocyclohexyl)amino]-6-(4-methoxybutylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(4-methoxybutylamino)-9-cyclopentylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0327] CIMS (NH₃) 388 (MH⁺); Rf (min.)=3.29

EXAMPLE 302-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0328] Scheme A, Step b:2-Chloro-6-[2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine

[0329] 2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine isprepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 forpreparation), 2,3-dimethoxybenzylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0330] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0331]2-[Trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride is prepared from2-chloro-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purine essentiallyas described in Example 1, Scheme A, step c.

[0332] CIMS (NH₃) 440 (MH⁺); Rf (min.)=3.39

EXAMPLE 312-[Trans-(4-aminocyclohexyl)amino]-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurineTrihydrochloride

[0333] Scheme A, Step b:2-Chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine

[0334] 2-Chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine, N-phenylethylenediamine,and triethylamine essentially as described above in Example 1, Scheme A,step b.

[0335] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurineTrihydrochloride

[0336]2-[Trans-(4-aminocyclohexyl)amino]-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[2-(phenylamino)ethylamino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0337] CIMS (NH₃) 435 (MH⁺); Rf (min.)=3.34

EXAMPLE 322-[Trans-(4-aminocyclohexyl)amino]-6-(phenylamino)-9-cyclopentylpurineDihydrochloride

[0338] Scheme A, Step b: 2-Chloro-6-(phenylamino)-9-cyclopentylpurine

[0339] 2-Chloro-6-(phenylamino)-9-cyclopentylpurine is prepared from2,6-dichloro-9-cyclopentylpurine, aniline, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0340] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(phenylamino)-9-cyclopentylpurineDihydrochloride

[0341]2-[Trans-(4-aminocyclohexyl)amino]-6-(phenylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(phenylamino)-9-cyclopentylpurine essentially as described inExample 1, Scheme A, step c.

[0342] CIMS (NH₃) 392 (MH⁺); Rf (min.)=3.35

EXAMPLE 332-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[0343] Scheme A, Step b:2-Chloro-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurine

[0344] 2-Chloro-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-benzylpiperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0345] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[0346]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-(1-benzyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0347] CIMS (NH₃) 489 (MH⁺); Rf (min.)=3.29

EXAMPLE 342-[Trans-(4-aminocyclohexyl)amino]-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0348] Scheme A, Step b:2-Chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine

[0349] 2-Chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,3,4-dimethoxybenzylamine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0350] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurineDihydrochloride

[0351]2-[Trans-(4-aminocyclohexyl)amino]-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-[3,4-dimethoxybenzyl)amino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[0352] CIMS (NH₃) 466 (MH⁺); Rf (min.)=2.25

EXAMPLE 352-[Trans-(4-aminocyclohexyl)amino]-6-[(3-iodobenzyl)amino]-9-(2-cyclopentenyl)purineHydrochloride

[0353] Scheme A, Step a: 2,6-Dichloro-9-cyclopentenylpurine

[0354] 2,6-Dichloro-9-cyclopentenylpurine is prepared from2,6-dichloropurine and cyclopentenol essentially as described in Example1, Scheme A, step a, but substituting cyclopentenol for cyclopentanol.

[0355] Scheme A, Step b:2-Chloro-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine

[0356] 2-Chloro-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine isprepared from 2,6-dichloro-9-cyclopentenylpurine, 3-iodobenzylamine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[0357] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine

[0358]2-[Trans-(4-aminocyclohexyl)amino]-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurinehydrochloride is prepared from2-chloro-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine essentially asdescribed in Example 1, Scheme A, step c.

[0359] CIMS (NH₃) 530 (MH⁺)

EXAMPLE 362-[Trans-(4-aminocyclohexyl)amino]-6-(dodecylamino)-9-cyclopentylpurineDihydrochloride

[0360] Scheme A, Step b: 2-Chloro-6-(dodecylamino)-9-cyclopentylpurine

[0361] 2-Chloro-6-dodecylamino)-9-cyclopentylpurine is prepared from2,6-dichloro-9-cyclopentylpurine, n-dodecylamine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0362] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(dodecylamino)-9-cyclopentylpurineDihydrochloride

[0363]2-[Trans-(4-aminocyclohexyl)amino]-6-(dodecylamino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(dodecylamino)-9-cyclopentylpurine essentially as describedin Example 1, Scheme A, step c.

[0364] CIMS (NH₃) 484 (MH⁺); Rf (min.)=5.09

EXAMPLE 372-[Trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0365] Scheme A, Step b:2-Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine

[0366] 2-Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine isprepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 forpreparation), 4-methoxybenzylamine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0367] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purineDihydrochloride

[0368]2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride is prepared from2-chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine essentially asdescribed in Example 1, Scheme A, step c.

[0369] CIMS (NH₃) 410 (MH⁺); Rf (min.)=3.37

EXAMPLE 382-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-chlorobenzyl)piperidinylamino]-9-cyclopentylpurine

[0370] Preparation of 4-Amino-1-(4-chlorobenzyl)piperidine

[0371] Method 1

[0372] Scheme B, Step a: 4-Carboxamide-1-(4-chlorobenzyl)piperidine

[0373] Dissolve isonipecotamide (39 mmol) in 3-pentanone (25 mL) andheat to reflux. Add cesium carbonate (24 mmol) and a catalytic amount ofpotassium iodide (2 spatula tips, cat) followed by 4-chlorobenzylchloride (47 mmol). Stir and reflux for 5 hours. Filter the hot solutionthrough celite, wash the filter cake with hot acetone (4×20 mL), combinethe filtrate and washings, and evaporate the solvent in vacuo andresidue was recrystallized from acetone to give the title compound.

[0374] Scheme B, Step b: 4-Amino-1-(4-chlorobenzyl)piperidine

[0375] Dissolve bis(trifluoroacetoxy)iodobenzene (84 mmol) inacetonitrile (20 mL) and dilute with water (20 mL). Add4-carboxamide-1-(4-chlorobenzyl)piperidine (7 mmol) and heat forovernight at 65° C. Cool the mixture (ice bath), add water (60 mL),followed by concentrated HCl. Extract with ether (2×). The aqueous layerwas concentrated in vacuo, and the residue was dissolved in water in 40mL of water. Basify with aqueous sodium carbonate, and extract intomethylene chloride, the organic layer was drived over Na₂SO₄, filteredand the solvent was evaporated in vacuo to give the title compound.

[0376] Method 2

[0377] Scheme C, Step a: 1-(4-Chlorobenzyl)-4-piperidone

[0378] Dissolve 4-piperidone (17 mmol) in 3-pentanone (25 mL) and heatto reflux. Add cesium carbonate (19 mmol) and a catalytic amount ofpotassium iodide, followed by 4-chlorobenzyl chloride (20 mmol). Stirand reflux for 4 hours. Filter the hot suspension, wash the residue withhot acetone (4×20 mL), combine the filtrate and washings, and evaporatethe solvent in vacuo to give the title compound.

[0379] Scheme C, Step b: 1-(4-Chlorobenzyl)-4-piperidone Oxime

[0380] Dissolve 1-(4-chlorobenzyl)-4-piperidone (0.0456 mmol),hydroxylamine hydrochloride (0.0456 mmol) and sodium acetate (0.0456mmol) in aqueous ethanol (450 mL). Stir approximately 30 minutes to 2hours while warming. Add methylene chloride (450 mL), separate theorganic phase, and extract the aqueous phase with methylene chloride(100 mL). Combine the organic phases and dry (MgSO₄). Evaporate thesolvent in vacuo to give the title compound.

[0381] Scheme C, Step c: 4-Amino-1-(4-chlorobenzyl)piperidine

[0382] Add 1-(4-chlorobenzyl)-4-piperidone oxime (1.87 mmol) to asolution of lithium aluminum hydride (2.5 mL of a 1M solution intetrahydrofuran) and place under a nitrogen atmosphere. Heat at refluxfor 2 hours, cool and pour into dilute aqueous sodium hydroxide. Extractwith a mixture of ethyl ether/ethyl acetate (2×), wash with aqueoussodium chloride and dry (MgSO₄). Evaporate the solvent in vacuo to givethe title compound.

[0383] Scheme A, Step b:2-Chloro-6-[4-(1-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0384]2-Chloro-6-[4-(1-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-chlorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0385] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0386]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0387] Rf: (min)=2.29; purity 94%; MS (APCI): 523 M+⁺¹

EXAMPLE 392-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0388] Preparation of 4-Amino-1-(4-methoxybenzyl)piperidine

[0389] Method 1

[0390] Scheme B, Step a: 4-Carboxamide-1-(4-methoxybenzyl)piperidine

[0391] 4-Carboxamide-1-(4-methoxybenzyl)piperidine may be prepared fromisonipecotamide and 4-methoxybenzyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[0392] Scheme B, Step b: 4-Amino-1-(4-methoxybenzyl)piperidine

[0393] 4-Amino-1-(4-methoxybenzyl)piperidine is prepared from4-carboxamide-1-(4-methoxybenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0394] Method 2

[0395] Scheme C, Step a: 1-(4-Methoxybenzyl)-4-piperidone

[0396] 1-(4-Methoxybenzyl)-4-piperidone is prepared from 4-piperidoneand 4-methoxybenzyl chloride essentially as described above in Example38, Scheme C, step a.

[0397] Scheme C, Step b: 1-(4-Methoxybenzyl)-4-piperidone Oxime

[0398] 1-(4-Methoxybenzyl)-4-piperidone oxime is prepared from1-(4-methoxybenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0399] Scheme C, Step c: 4-Amino-1-(4-methoxybenzyl)piperidine

[0400] 4-Amino-1-(4-methoxybenzyl)piperidine is prepared from1-(4-methoxybenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0401] Scheme A, Step b:2-Chloro-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0402]2-Chloro-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-methoxybenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0403] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0404]2-[Trans-(aminocyclohexyl)amino]-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0405] Rf: (min)=2.26; purity 100%; MS (APCI): 519 M⁺¹

EXAMPLE 402-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0406] Preparation of 4-Amino-1-(4-methylbenzyl)piperidine

[0407] Method 1

[0408] Scheme B, Step a: 4-Carboxamide-1-(4-methylbenzyl)piperidine

[0409] 4-Carboxamide-1-(4-methylbenzyl)piperidine may be prepared fromisonipecotamide and α-chloro-p-xylene essentially as described above inExample 38, Scheme B, step a.

[0410] Scheme B, Step b: 4-Amino-1-(4-methylbenzyl)piperidine

[0411] 4-Amino-1-(4-methylbenzyl)piperidine is prepared from4-carboxamide-1-(4-methylbenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0412] Method 2

[0413] Scheme C, Step a: 1-(4-Methylbenzyl)-4-piperidone

[0414] 1-(4-Methylbenzyl)-4-piperidone is prepared from 4-piperidone andα-chloro-p-xylene essentially as described above in Example 38, SchemeC, step a.

[0415] Scheme C, Step b: 1-(4-Methylbenzyl)-4-piperidone Oxime

[0416] 1-(4-Methylbenzyl)-4-piperidone oxime is prepared from1-(4-methylbenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0417] Scheme C, Step c: 4-Amino-1-(4-methylbenzyl)piperidine

[0418] 1-Amino-1-(4-methylbenzyl)piperidine is prepared from1-(4-methylbenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0419] Scheme A, Step b:2-Chloro-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0420]2-Chloro-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-methylbenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0421] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0422]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-methylbenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0423] Rf: (min)=2.26; purity 100%; MS (APCI): 503 M⁺¹

EXAMPLE 412-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0424] Preparation of 4-Amino-1-(3-methoxybenzyl)piperidine

[0425] Method 1

[0426] Scheme B, Step a: 4-Carboxamide-1-(3-methoxybenzyl)piperidine

[0427] 4-Carboxamide-1-(3-methoxybenzyl)piperidine may be prepared fromisonipecotamide and 3-methoxybenzyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[0428] Scheme B, Step b: 4-Amino-1-(3-methoxybenzyl)piperidine

[0429] 4-Amino-1-(3-methoxybenzyl)piperidine is prepared from4-carboxamide-1-(3-methoxybenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0430] Method 2

[0431] Scheme C, Step a: 1-(3-Methoxybenzyl)-4-piperidone

[0432] 1-(3-Methoxybenzyl)-4-piperidone is prepared from 4-piperidoneand 3-methoxybenzyl chloride essentially as described above in Example38, Scheme C, step a.

[0433] Scheme C, Step b: 1-(3-Methoxybenzyl)-4-piperidone Oxime

[0434] 1-(3-Methoxybenzyl)-4-piperidone oxime is prepared from1-(3-methoxybenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0435] Scheme C, Step c: 4-Amino-1-(3-methoxybenzyl)piperidine

[0436] 4-Amino-1-(3-methoxybenzyl)piperidine is prepared from1-(3-methoxybenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0437] Scheme A, Step b:2-Chloro-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0438]2-Chloro-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-methoxybenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0439] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurine

[0440]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-methoxybenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0441] Rf: (min)=2.27; purity 99%; MS (APCI): 519 M⁺¹

EXAMPLE 422-[Trans-(4-aminocyclohexyl)amino]-6-[4-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0442] Preparation of 4-Amino-1-(3-chlorobenzyl)piperidine

[0443] Method 1

[0444] Scheme B, Step a: 4-Carboxamide-1-(3-chlorobenzyl)piperidine

[0445] 4-Carboxamide-1-(3-chlorobenzyl)piperidine may be prepared fromisonipecotamide and 3-chlorobenzyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[0446] Scheme B, Step b: 4-Amino-1-(3-chlorobenzyl)piperidine

[0447] 4-Amino-1-(3-chlorobenzyl)piperidine is prepared from4-carboxamide-1-(3-chlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0448] Method 2

[0449] Scheme C, Step a: 1-(3-Chlorobenzyl)-4-piperidone

[0450] 1-(3-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and3-chlorobenzyl chloride essentially as described above in Example 38,Scheme C, step a.

[0451] Scheme C, Step b: 1-(3-Chlorobenzyl)-4-piperidone Oxime

[0452] 1-(3-Chlorobenzyl)-4-piperidone oxime is prepared from13-chlorobenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0453] Scheme C, Step c: 4-Amino-1-(3-chlorobenzyl)piperidine

[0454] 4-Amino-1-(3-chlorobenzyl)piperidine is prepared from1-(3-chlorobenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0455] Scheme A, Step b:2-Chloro-6-[4-(1-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0456]2-Chloro-6-[4-(1-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-chlorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0457] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0458]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0459] Rf: (min)=2.25; purity 95%; MS (APCI): 523 M⁺¹

EXAMPLE 432-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0460] Preparation of 4-Amino-1-(2-chlorobenzyl)piperidine

[0461] Method 1

[0462] Scheme B, Step a: 4-Carboxamide-1-(2-chlorobenzyl)piperidine

[0463] 4-Carboxamide-1-(2-chlorobenzyl)piperidine may be prepared fromisonipecotamide and 2-chlorobenzyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[0464] Scheme B, Step b: 4-Amino-1-(2-chlorobenzyl)piperidine

[0465] 4-Aminoe-1-(2-chlorobenzyl)piperidine is prepared from4-carboxamide-1-(2-chlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0466] Method 2

[0467] Scheme C, Step a: 1-(2-chlorobenzyl)-4-piperidone

[0468] 1-(2-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and2-chlorobenzyl chloride essentially as described above in Example 38,Scheme C, step a.

[0469] Scheme C, Step b: 1-(2-Chlorobenzyl)-4-piperidone Oxime

[0470] 1-(2-Chlorobenzyl)-4-piperidone oxime is prepared from1-(2-chlorobenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0471] Scheme C, Step c: 4-Amino-1-(2-chlorobenzyl)piperidine

[0472] 4-Amino-1-(2-chlorobenzyl)piperidine is prepared from1-(2-chlorobenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0473] Scheme A, Step b:2-Chloro-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0474]2-Chloro-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-chlorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0475] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0476]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-chlorobenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0477] Rf: (min)=2.25; purity 92%; MS (APCI): 523 M⁺¹

EXAMPLE 44 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0478] Preparation of 4-Amino-1-(2-methylbenzyl)piperidine

[0479] Method 1

[0480] Scheme B, Step a: 4-Carboxamide-1-(2-methylbenzyl)piperidine

[0481] 4-Carboxamide-1-(2-methylbenzyl)piperidine may be prepared fromisonipecotamide and α-chloro-o-xylene essentially as described above inExample 38, Scheme B, step a.

[0482] Scheme B, Step b: 4-Amino-1-(2-methylbenzyl)piperidine

[0483] 4-Amino-1-(2-methylbenzyl)piperidine is prepared from4-carboxamide-1-(2-methylbenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0484] Method 2

[0485] Scheme C, Step a: 1-(2-Methylbenzyl)-4-piperidone

[0486] 1-(2-Methylbenzyl)-4-piperidone is prepared from 4-piperidone andα-chloro-o-xylene essentially as described above in Example 38, SchemeC, step a.

[0487] Scheme C, Step b: 4-Amino-1-(2-methylbenzyl)piperidine Oxime

[0488] 4-Amino-1-(2-methylbenzyl)piperidine oxime is prepared from4-amino-1-(2-methylbenzyl)piperidine and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0489] Scheme C, Step c: 4-Amino-1-(2-methylbenzyl)piperidine

[0490] 4-Amino-1-(2-methylbenzyl)piperidine is prepared from essentiallyas described above in Example 38, Scheme C, step c.

[0491] Scheme A, Step b:2-Chloro-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0492]2-Chloro-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-methylbenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0493] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0494]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-methylbenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0495] Rf: (min)=2.26; purity 98%; MS (APCI): 503 M⁺¹

EXAMPLE 452-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0496] Preparation of 4-Amino-1-(2,6-dichlorobenzyl)piperidine

[0497] Method 1

[0498] Scheme B, Step a: 4-Carboxamide-1-(2,6-dichlorobenzyl)piperidine

[0499] 4-Carboxamide-1-(2,6-dichlorobenzyl)piperidine may be preparedfrom isonipecotamide and α,2,6-trichlorotoluene essentially as describedabove in Example 38, Scheme B, step a.

[0500] Scheme B, Step b: 4-Amino-1-(2,6-dichlorobenzyl)piperidine

[0501] 4-Amino-1-(2,6-dichlorobenzyl)piperidine is prepared from4-carboxamide-1-(2,6-dichlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0502] Method 2

[0503] Scheme C, Step a: 1-(2,6-Dichlorobenzyl)-4-piperidone

[0504] 1-(2,6-Dichlorobenzyl)-4-piperidone is prepared from 4-piperidoneand α,2,6-trichlorotoluene essentially as described above in Example 38,Scheme C, step a.

[0505] Scheme C, Step b: 1-(2,6-Dichlorobenzyl)-4-piperidone Oxime

[0506] 1-(2,6-Dichlorobenzyl)-4-piperidone oxime is prepared from I-(2,6-dichlorobenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0507] Scheme C, Step c: 4-Amino-1-(2,6-dichlorobenzyl)piperidine

[0508] 4-Amino-1-(2,6-dichlorobenzyl)piperidine is prepared from1-(2,6-dichlorobenzyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0509] Scheme A, Step b:2-Chloro-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0510]2-Chloro-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,6-dichlorobenzyl)piperidine (made according to the Method 1of Example 45), and triethylamine essentially as described above inExample 1, Scheme A, step b.

[0511] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurine

[0512]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2,6-dichlorobenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0513] Rf: (min)=2.28; purity 98%; MS (APCI): 557 M⁺¹.

EXAMPLE 462-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0514] Preparation of 4-Amino-1-(4-trifluoromethylbenzyl)piperidine

[0515] Method 1

[0516] Scheme B, Step a:4-Carboxamide-1-(4-trifluoromethylbenzyl)piperidine

[0517] 4-Carboxamide-1-(4-trifluoromethylbenzyl)piperidine may beprepared from isonipecotamide and α′-chloro-α,α,α-trifluoro-p-xyleneessentially as described above in Example 38, Scheme B, step a.

[0518] Scheme B, Step b: 4-Amino-1-(4-trifluoromethylbenzyl)piperidine

[0519] 4-Amino-1-(4-trifluoromethylbenzyl)piperidine is prepared from4-carboxamide-1-(4-trifluoromethylbenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[0520] Method 2

[0521] Scheme C, Step a: 1-(4-Trifluoromethylbenzyl)-4-piperidone

[0522] 1-(4-Trifluoromethylbenzyl)-4-piperidone is prepared from4-piperidone and α′-chloro-α,α,α-trifluoro-p-xylene essentially asdescribed above in Example 38, Scheme C, step a.

[0523] Scheme C, Step b: 1-(4-Trifluoromethylbenzyl)-4-piperidone Oxime

[0524] 1-(4-Trifluoromethylbenzyl)-4-piperidone oxime is prepared from1-(4-trifluoromethylbenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0525] Scheme C, Step c: 4-Amino-1-(4-trifluoromethylbenzyl)piperidine

[0526] 4-Amino-1-(4-trifluoromethylbenzyl)piperidine is prepared from1-(4-trifluoromethylbenzyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[0527] Scheme A, Step b:2-Chloro-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino-9-cyclopentylpurine

[0528]2-Chloro-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-trifluoromethylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0529] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0530]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-trifluoromethylbenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0531] Rf: (min)=2.38; purity 100%; MS (APCI): 557 M⁻¹

EXAMPLE 47(+/−)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(α-methylbenzyl)piperidinylamino]-9-cyclopentylpurine

[0532] Preparation of (R,S)-4-Amino-1-(α-methylbenzyl)piperidine

[0533] Method 1

[0534] Scheme B, Step a: 4-Carboxamide-1-(α-methylbenzyl)piperidine

[0535] 4-Carboxamide-1-(α-methylbenzyl)piperidine may be prepared fromisonipecotamide and α-methylbenzyl bromide essentially as describedabove in Example 38, Scheme B, step a.

[0536] Scheme B, Step b: (R,S)-4-Amino-1-(α-methylbenzyl)piperidine

[0537] (R,S)-4-Amino-1-(α-methylbenzyl)piperidine is prepared from4-carboxamide-1-(α-methylbenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0538] Method 2

[0539] Scheme C, Step a: 1-(α-Methylbenzyl)-4-piperidone

[0540] 1-(α-Methylbenzyl)-4-piperidone is prepared from 4-piperidone andα-methylbenzyl bromide essentially as described above in Example 38,Scheme C, step a.

[0541] Scheme C, Step b: 1-(α-Methylbenzyl)-4-piperidone Oxime

[0542] 1-(α-Methylbenzyl)-4-piperidone oxime is prepared from1-(α-methylbenzyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0543] Scheme C, Step c: (R,S)-4-Amino-1-(α-methylbenzyl)piperidine

[0544] (R,S)-4-Amino-1-(α-methylbenzyl)piperidine is prepared from1-(α-methylbenzyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step C.

[0545] Scheme A, Step b:2-Chloro-6-[4-(1-(α-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0546]2-Chloro-6-[4-(1-(α-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-4-amino-1-(α-methylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0547] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-α-methylbenzyl))piperidinylamino]-9-cyclopentylpurine

[0548]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(α-methylbenzyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(α-methylbenzyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 482-[Trans-(4-aminocyclohexyl)amino]-6-[(1-(3-phenoxypropyl)piperidinylamino]-9-cyclopentylpurine

[0549] Preparation of 4-Amino-1-(3-phenoxypropyl)piperidine

[0550] Method 1

[0551] Scheme B, Step a: 4-Carboxamide-1-(3-phenoxypropyl)piperidine

[0552] 4-Carboxamide-1-(3-phenoxypropyl)piperidine may be prepared fromisonipecotamide and 1-chloro-3-phenoxypropane essentially as describedabove in Example 38, Scheme B, step a.

[0553] Scheme B, Step b: 4-Amino-1-(3-phenoxypropyl)piperidine

[0554] 4-Amino-1-(3-phenoxypropyl)piperidine is prepared from4-carboxamide-1-(3-phenoxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0555] Method 2

[0556] Scheme C, Step a: 1-(3-Phenoxypropyl)-4-piperidone

[0557] 1-(3-Phenoxypropyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-3-phenoxypropane essentially as described above in Example38, Scheme C, step a.

[0558] Scheme C, Step b: 1-(3-Phenoxypropyl)-4-piperidone Oxime

[0559] 1-(3-Phenoxypropyl)-4-piperidone oxime is prepared from1-(3-phenoxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0560] Scheme C, Step c: 4-Amino-1-(3-phenoxypropyl)piperidine

[0561] 4-Amino-1-(3-phenoxypropyl)piperidine is prepared from1-(3-phenoxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0562] Scheme A, Step b:2-Chloro-6-[4-(1-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine

[0563]2-Chloro-6-[4-(1-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-phenoxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0564] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurine

[0565]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-phenoxypropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 492-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurine

[0566] Preparation of 4-Amino-1-(2-phenoxyethyl)piperidine

[0567] Method 1

[0568] Scheme B, Step a: 4-Carboxamide-1-(2-phenoxyethyl)piperidine

[0569] 4-Carboxamide-1-(2-phenoxyethyl)piperidine may be prepared fromisonipecotamide and 1-chloro-2-phenoxyethane essentially as describedabove in Example 38, Scheme B, step a.

[0570] Scheme B, Step b: 4-Amino-1-(2-phenoxyethyl)piperidine

[0571] 4-Amino-1-(2-phenoxyethyl)piperidine is prepared from4-carboxamide-1-(2-phenoxyethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0572] Method 2

[0573] Scheme C, Step a: 1-(2-Phenoxyethyl)-4-piperidone

[0574] 1-(2-Phenoxyethyl)-4-piperidone is prepared from 4-piperidone and1-chloro-2-phenoxyethane essentially as described above in Example 38,Scheme C, step a.

[0575] Scheme C, Step b: 1-(2-Phenoxyethyl)-4-piperidone Oxime

[0576] 1-(2-Phenoxyethyl)-4-piperidone oxime is prepared from1-(2-phenoxyethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0577] Scheme C, Step c: 4-Amino-1-(2-phenoxyethyl)piperidine

[0578] 4-Amino-1-(2-phenoxyethyl)piperidine is prepared from1-(2-phenoxyethyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0579] Scheme A, Step b:2-Chloro-6-[4-(1-(2-phenoxyethyl)piperidinylamino]-9-cyclopentylpurine

[0580]2-Chloro-6-[4-(1-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-phenoxyethyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0581] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurine

[0582]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-phenoxyethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 502-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurine

[0583] Preparation of 4-Amino-1-(2-phenylethyl)piperidine

[0584] Method 1

[0585] Scheme B, Step a: 4-Carboxamide-1-(2-phenylethyl)piperidine

[0586] 4-Carboxamide-1-(2-phenylethyl)piperidine may be prepared fromisonipecotamide and (2-chloroethyl)benzene essentially as describedabove in Example 38, Scheme B, step a.

[0587] Scheme B, Step b: 4-Amino-1-(2-phenylethyl)piperidine

[0588] 4-Amino-1-(2-phenylethyl)piperidine is prepared from4-carboxamide-1-(2-phenylethyl)piperidine essentially as described abovein Example 38, Scheme B, step b.

[0589] Method 2

[0590] Scheme C, Step a: 1-(2-Phenylethyl)-4-piperidone

[0591] 1-(2-phenylethyl)-4-piperidone is prepared from 4-piperidone and(2-chloroethyl)benzene essentially as described above in Example 38,Scheme C, step a.

[0592] Scheme C, Step b: 1-(2-Phenylethyl)-4-piperidone Oxime

[0593] 1-(2-Phenylethyl)-4-piperidone oxime is prepared from1-(2-phenylethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0594] Scheme C, Step c: 4-Amino-1-(2-phenylethyl)piperidine

[0595] 4-Amino-1-(2-phenylethyl)piperidine is prepared from1-(2-phenylethyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0596] Scheme A, Step b:2-Chloro-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurine

[0597]2-Chloro-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-phenylethyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0598] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurine

[0599]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-phenylethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 512-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurine

[0600] Preparation of 4-Amino-1-propylpiperidine

[0601] Method 1

[0602] Scheme B, Step a: 4-Carboxamide-1-propylpiperidine

[0603] 4-Carboxamide-1-propylpiperidine may be prepared fromisonipecotamide and 1-chloropropane essentially as described above inExample 38, Scheme B, step a.

[0604] Scheme B, Step b: 4-Amino-1-propylpiperidine

[0605] 4-Amino-1-propylpiperidine is prepared from4-carboxamide-1-propylpiperidine essentially as described above inExample 38, Scheme B, step b.

[0606] Method 2

[0607] Scheme C, Step a: 1-Propyl-4-piperidone

[0608] 1-Propyl-4-piperidone is prepared from 4-piperidone and1-chloropropane essentially as described above in Example 38, Scheme C,step a.

[0609] Scheme C, Step b: 1-Propyl-4-piperidone Oxime

[0610] 1-Propyl-4-piperidone oxime is prepared from1-propyl-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

[0611] Scheme C, Step c: 4-Amino-1-propylpiperidine

[0612] 4-Amino-1-propylpiperidine is prepared from 1-propyl-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[0613] Scheme A, Step b:2-Chloro-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurine

[0614] 2-Chloro-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-propylpiperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0615] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurine

[0616]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 522-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurine

[0617] Preparation of 4-Amino-1-cyclopropylmethylpiperidine

[0618] Method 1

[0619] Scheme B, Step a: 4-Carboxamide-1-cyclopropylmethylpiperidine

[0620] 4-Carboxamide-1-cyclopropylmethylpiperidine may be prepared fromisonipecotamide and (chloromethyl)cyclopropane essentially as describedabove in Example 38, Scheme B, step a.

[0621] Scheme B, Step b: 4-Amino-1-cyclopropylmethylpiperidine

[0622] 4-Amino-1-cyclopropylmethylpiperidine is prepared from4-carboxamide-1-cyclopropylmethylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[0623] Method 2

[0624] Scheme C, Step a: 1-(Cyclopropylmethyl)-4-piperidone

[0625] 1-(Cyclopropylmethyl)-4-piperidone is prepared from 4-piperidoneand (chloromethyl)cyclopropane essentially as described above in Example38, Scheme C, step a.

[0626] Scheme C, Step b: 1-(Cyclopropylmethyl)piperidone Oxime

[0627] 1-(Cyclopropylmethyl)-4-piperidone oxime is prepared from1-(cyclopropylmethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0628] Scheme C, Step c: 4-Amino-1-cyclopropylmethylpiperidine

[0629] 4-Amino-1-cyclopropylmethylpiperidine is prepared from1-(cyclopropylmethyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0630] Scheme A, Step b:2-Chloro-6-[4-(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurine

[0631]2-Chloro-6-[(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-cyclopropylmethylpiperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0632] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurine

[0633]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-cyclopropylmethyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[0634] Rf: (min)=2.19; purity 100%; MS (APCI): 454 M⁺¹

EXAMPLE 532-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-pyridinylmethyl)piperidinylamino]-9-cyclopentylpurine

[0635] Preparation of 4-Amino-1-(2-pyridinylmethyl)piperidine

[0636] Method 1

[0637] Scheme B, Step a: 4-Carboxamide-1-(2-pyridinylmethyl)piperidine

[0638] 4-Carboxamide-1-(2-pyridinylmethyl)piperidine may be preparedfrom isonipecotamide and 2-picolyl chloride hydrochloride essentially asdescribed above in Example 38, Scheme B, step a.

[0639] Scheme B, Step b: 4-Amino-1-(2-pyridinylmethyl)piperidine

[0640] 4-amino-1-(2-pyridinylmethyl)piperidine is prepared from4-carboxamide-1-(2-pyridinylmethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0641] Method 2

[0642] Scheme C, Step a: 1-(2-Pyridinylmethyl)-4-piperidone

[0643] 1-(2-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidoneand 2-picolyl chloride hydrochloride essentially as described above inExample 38, Scheme C, step a.

[0644] Scheme C, Step b: 1-(2-Pyridinylmethyl)-4-piperidone Oxime

[0645] 1-(2-Pyridinylmethyl)-4-piperidone oxime is prepared from1-(2-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0646] Scheme C, Step c: 4-Amino-1-(2-pyridinylmethyl)piperidine

[0647] 4-Amino-1-(2-pyridinylmethyl)piperidine is prepared from1-(2-pyridinylmethyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0648] Scheme A, Step b:2-Chloro-6-[4-(1-(2-pyridinylmethyl)piperidinylamino]-9-cyclopentylpurine

[0649]2-Chloro-6-[4-(1-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-pyridinylmethyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0650] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine

[0651]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 54 2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-pyridinylmethyl)piperidinylamino]-9-cyclopentylpurine

[0652] Preparation of 4-Amino-1-(3-pyridinylmethyl)piperidine

[0653] Method 1

[0654] Scheme B, Step a: 4-Carboxamide-1-(3-pyridinylmethyl)piperidine

[0655] 4-Carboxamide-1-(3-pyridinylmethyl)piperidine may be preparedfrom isonipecotamide and 3-picolyl chloride hydrochloride essentially asdescribed above in Example 38, Scheme B, step a.

[0656] Scheme B, Step b: 4-Amino-1-(3-pyridinylmethyl)piperidine

[0657] 4-Amino-1-(3-pyridinylmethyl)piperidine is prepared from4-carboxamide-1-(3-pyridinylmethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0658] Method 2

[0659] Scheme C, Step a: 1-(3-Pyridinylmethyl)-4-piperidone

[0660] 1-(3-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidoneand 3-picolyl chloride hydrochloride essentially as described above inExample 38, Scheme C, step a.

[0661] Scheme C, Step b: 1-(3-Pyridinylmethyl)-4-piperidone Oxime

[0662] 1-(3-Pyridinylmethyl)-4-piperidone oxime is prepared from1-(3-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0663] Scheme C, Step c: 4-Amino-1-(3-pyridinylmethyl)piperidine

[0664] 4-Amino-1-(3-pyridinylmethyl)piperidine is prepared from1-(3-pyridinylmethyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0665] Scheme A, Step b:2-Chloro-6-[4-(1-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine

[0666]2-Chloro-6-[4-(1-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-pyridinylmethyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0667] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine

[0668]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 552-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-pyridinylmethyl)piperidinylamino]-9-cyclopentylpurine

[0669] Preparation of 4-Amino-1-(pyridinylmethyl)piperidine

[0670] Method 1

[0671] Scheme B, Step a: 4-Carboxamide-1-(4-pyridinylmethyl)piperidine

[0672] 4-Carboxamide-1-(4-pyridinylmethyl)piperidine may be preparedfrom isonipecotamide and 4-picolyl chloride hydrochloride essentially asdescribed above in Example 38, Scheme B, step a.

[0673] Scheme B, Step b: 4-Amino-1-(4-pyridinylmethyl)piperidine

[0674] 4-Amino-1-(4-pyridinylmethyl)piperidine is prepared from4-carboxamide-1-(4-pyridinylmethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0675] Method 2

[0676] Scheme C, Step a: 1-(4-Pyridinylmethyl)-4-piperidone

[0677] 1-(4-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidoneand 4-picolyl chloride hydrochloride essentially as described above inExample 38, Scheme C, step a.

[0678] Scheme C, Step b: 1-(4-pyridinylmethyl)-4-piperidone Oxime

[0679] 1-(4-Pyridinylmethyl)-4-piperidone oxime is prepared from1-(4-pyridinylmethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0680] Scheme C, Step c: 4-Amino-1-(4-pyridinylmethyl)piperidine

[0681] 4-Amino-1-(4-pyridinylmethyl)piperidine is prepared from1-(4-pyridinylmethyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0682] Scheme A, Step b:2-Chloro-6-[4-(1-(4-pyridinylmethyl)piperidinylamino]-9-cyclopentylpurine

[0683]2-Chloro-6-[4-(1-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-pyridinylmethyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0684] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurine

[0685]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-pyridinylmethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 562-[Trans-(4-aminocyclohexyl)amino]-6-[4-[(1-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurine

[0686] Preparation of4-Amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine

[0687] Method 1

[0688] Scheme B, Step a:4-Carboxamide-1-(3-(2,4-dimethylisoxazolyl)methyl)piperidine

[0689] 4-Carboxamide-1-(3-(2,4-dimethylisoxazolyl)methyl)piperidine maybe prepared from isonipecotamide and2,4-dimethyl-3-chloromethyl-isoxazole essentially as described above inExample 38, Scheme B, step a.

[0690] Scheme B, Step b:4-Amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine

[0691] 4-Amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine is preparedfrom 4-carboxamide-1-(3-(2,4-dimethylisoxazolyl)methyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[0692] Method 2

[0693] Scheme C, Step a:1-(3-(2,4-Dimethylisoxazolyl)methyl)-4-piperidone

[0694] 1-(3-(2,4-Dimethylisoxazolyl)methyl)-4-piperidone is preparedfrom 4-piperidone and 2,4-dimethyl-3-chloromethyl-isoxazole essentiallyas described above in Example 38, Scheme C, step a.

[0695] Scheme C, Step b:1-(3-(2,4-Dimethylisoxazolyl)methyl)-4-piperidone Oxime

[0696] 1-(3-(2,4-Dimethylisoxazolyl)methyl)-4-piperidone oxime isprepared from 1-(3-(2,4-dimethylisoxazolyl)methyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[0697] Scheme C, Step c:4-Amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine

[0698] 4-Amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine is preparedfrom 1-(3-(2,4-dimethylisoxazolyl)methyl)-4-piperidone oxime essentiallyas described above in Example 38, Scheme C, step c.

[0699] Scheme A, Step b:2-Chloro-6-[4-(1-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurine

[0700]2-Chloro-6-[4-(1-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-(2,4-dimethylisoxazolyl)methylpiperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0701] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(2,4-dimethylisoxazolyl)methyl)piperidinylamino]-9-cyclopentylpurine

[0702]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-(2,4-dimethylisoxazolyl))methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 57(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurine

[0703] Preparation of (R,S)-4-Amino-1-benzyl-3-methylpiperidine

[0704] Method 1

[0705] Scheme B, Step a: (R,S)-4-Carboxamide-1-benzyl-3-methylpiperidine

[0706] (R,S)-4-Carboxamide-1-benzyl-3-methylpiperidine may be preparedfrom (R,S)-4-carboxamide-3-methylpiperidine and benzyl chlorideessentially as described above in Example 38, Scheme B, step a,substituting (R,S)-4-carboxamide-3-methylpiperidine for isonipecotamide.

[0707] Scheme B, Step b: (R,S)-4-Amino-1-benzyl-3-methylpiperidine

[0708] (R,S)-4-Amino-1-benzyl-3-methylpiperidine is prepared from(R,S)-4-carboxamide-1-benzyl-3-methylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[0709] Method 2

[0710] Scheme C, Step a: (R,S)-1-Benzyl-3-methyl-4-piperidone

[0711] (R,S)-1-Benzyl-3-methyl-4-piperidone is prepared from(R,S)-3-methyl-4-piperidone and benzyl chloride essentially as describedabove in Example 38, Scheme C, step a, substituting(R,S)-3-methyl-4-piperidone for 4-piperidone.

[0712] Scheme C, Step b: (R,S)-1-Benzyl-3-methyl-4-piperidone Oxime

[0713] (R,S)-1-Benzyl-3-methyl-4-piperidone oxime is prepared from(R,S)-1-benzyl-3-methyl-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0714] Scheme C, Step c: (R,S)-4-Amino-1-benzyl-3-methylpiperidine

[0715] (R,S)-4-Amino-1-benzyl-3-methylpiperidine is prepared from(R,S)-1-benzyl-3-methyl-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[0716] Scheme A, Step b:(R,S)-2-Chloro-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurine

[0717](R,S)-2-Chloro-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-4-amino-1-benzyl-3-methylpiperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0718] Scheme A, Step c:(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurine

[0719](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurineis prepared from(R,S)-2-chloro-6-[4-(1-benzyl-3-methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 58a(R)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0720] Scheme A, Step b:(R)-2-Chloro-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0721](R)-2-Chloro-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,(R)-4-amino-1-benzyl-pyrrolidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0722] Scheme A, Step c:(R)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0723](R)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurineis prepared from(R)-2-chloro-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 58b(S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0724] Scheme A, Step b:(S)-2-Chloro-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0725](S)-2-Chloro-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,(S)-4-amino-1-benzyl-pyrrolidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0726] Scheme A, Step c:(S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurine

[0727](S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurineis prepared from(S)-2-chloro-6-[3-(1-benzyl)pyrrolidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 592-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurine

[0728] Preparation of 4-Amino-1-butylpiperidine

[0729] Method 1

[0730] Scheme B, Step a: 4-Carboxamide-1-butylpiperidine

[0731] 4-Carboxamide-1-butylpiperidine may be prepared fromisonipecotamide and 1-chlorobutane essentially as described above inExample 38, Scheme B, step a.

[0732] Scheme B, Step b: 4-Amino-1-butylpiperidine

[0733] 4-Amino-1-butylpiperidine is prepared from4-carboxamide-1-butylpiperidine essentially as described above inExample 38, Scheme B, step b.

[0734] Method 2

[0735] Scheme C, Step a: 1-Butyl-4-piperidone

[0736] 1-Butyl-4-piperidone is prepared from 4-piperidone and1-chlorobutane essentially as described above in Example 38, Scheme C,step a.

[0737] Scheme C, Step b: 1-Butyl-4-piperidone Oxime

[0738] 1-Butyl-4-piperidone oxime is prepared from 1-butyl-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[0739] Scheme C, Step c: 4-Amino-1-butylpiperidine

[0740] 4-Amino-1-butylpiperidine is prepared from 1-butyl-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[0741] Scheme A, Step b:2-Chloro-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurine

[0742] 2-Chloro-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-butylpiperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[0743] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurine

[0744]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-butyl)piperidinylamino]-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

EXAMPLE 602-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurine

[0745] Preparation of 4-Amino-1-(2-methylthioethyl)piperidine

[0746] Method 1

[0747] Scheme B, Step a: 4-Carboxamide-1-(2-methylthioethyl)piperidine

[0748] 4-Carboxamide-1-(2-methylthioethyl)piperidine may be preparedfrom isonipecotamide and 1-chloro-2-methylthioethane essentially asdescribed above in Example 38, Scheme B, step a.

[0749] Scheme B, Step b: 4-Amino-1-(2-methylthioethyl)piperidine

[0750] 4-Amino-1-(2-methylthioethyl)piperidine is prepared from4-carboxamide-1-(2-methylthioethyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0751] Method 2

[0752] Scheme C, Step a: 1-(2-methylthioethyl)-4-piperidone

[0753] 1-(2-Methylthioethyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-2-methylthioethane essentially as described above inExample 38, Scheme C, step a.

[0754] Scheme C, Step b: 1-(2-methylthioethyl)-4-piperidone Oxime

[0755] 1-(2-Methylthioethyl)-4-piperidone oxime is prepared from1-(2-methylthioethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0756] Scheme C, Step c: 4-Amino-1-(2-methylthioethyl)piperidine

[0757] 4-Amino-1-(2-methylthioethyl)piperidine is prepared from1-(2-methylthioethyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0758] Scheme A, Step b:2-Chloro-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurine

[0759]2-Chloro-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-methylthioethyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0760] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurine

[0761]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-methylthioethyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 612-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurine

[0762] Preparation of 4-Amino-1-(2-phenylsulfinylethyl)piperidine

[0763] Method 1

[0764] Scheme B, Step a:4-Carboxamide-1-(2-phenylsulfinylethyl)piperidine

[0765] 4-Carboxamide-1-(2-phenylsulfinylethyl)piperidine may be preparedfrom isonipecotamide and 1-chloro-2-phenylsulfinylethane essentially asdescribed above in Example 38, Scheme B, step a.

[0766] Scheme B, Step b: 4-Amino-1-(2-phenylsulfinylethyl)piperidine

[0767] 4-Amino-1-(2-phenylsulfinylethyl)piperidine is prepared from4-carboxamide-1-(2-phenylsulfinylethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[0768] Method 2

[0769] Scheme C, Step a: 1-(2-Phenylsulfinylethyl)-4-piperidone

[0770] 1-(2-Phenylsulfinylethyl)-4-piperidone is prepared from4-piperidone and 1-chloro-2-phenylsulfinylethane essentially asdescribed above in Example 38, Scheme C, step a.

[0771] Scheme C, Step b: 1-(2-Phenylsulfinylethyl)-4-piperidone Oxime

[0772] 1-(2-Phenylsulfinylethyl)-4-piperidone oxime is prepared from1-(2-phenylsulfinylethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0773] Scheme C, Step c: 4-Amino-1-(2-phenylsulfinylethyl)piperidine

[0774] 4-Amino-1-(2-phenylsulfinylethyl)piperidine is prepared from1-(2-phenylsulfinylethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[0775] Scheme A, Step b:2-Chloro-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurine

[0776]2-Chloro-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-phenylsulfinylethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0777] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurine

[0778]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-phenylsulfinyl)ethyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 622-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0779] Preparation of 4-Amino-1-(3-hydroxypropyl)piperidine

[0780] Method 1

[0781] Scheme B, Step a: 4-Carboxamide-1-(3-hydroxypropyl)piperidine

[0782] 4-Carboxamide-1-(3-hydroxypropyl)piperidine may be prepared fromisonipecotamide and 3-chloro-1-propanol essentially as described abovein Example 38, Scheme B, step a.

[0783] Scheme B, Step b: 4-Amino-1-(3-hydroxypropyl)piperidine

[0784] 4-Amino-1-(3-hydroxypropyl)piperidine is prepared from4-carboxamide-1-(3-hydroxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0785] Method 2

[0786] Scheme C, Step a: 1-(3-Hydroxypropyl)-4-piperidone

[0787] 1-(3-Hydroxypropyl)-4-piperidone is prepared from 4-piperidoneand 3-chloro-1-propanol essentially as described above in Example 38,Scheme C, step a.

[0788] Scheme C, Step b: 1-(3-Hydroxypropyl)-4-piperidone Oxime

[0789] 1-(3-Hydroxypropyl)-4-piperidone oxime is prepared from1-(3-hydroxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0790] Scheme C, Step c: 4-Amino-1-(3-hydroxypropyl)piperidine

[0791] 4-Amino-1-(3-hydroxypropyl)piperidine is prepared from1-(3-hydroxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0792] Scheme A, Step b:2-Chloro-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0793]2-Chloro-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-hydroxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0794] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0795]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-hydroxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 632-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0796] Preparation of 4-Amino-1-(3-methoxypropyl)piperidine

[0797] Method 1

[0798] Scheme B, Step a: 4-Carboxamide-1-(3-methoxypropyl)piperidine

[0799] 4-Carboxamide-1-(3-methoxypropyl)piperidine may be prepared fromisonipecotamide and 1-chloro-3-methoxypropane essentially as describedabove in Example 38, Scheme B, step a.

[0800] Scheme B, Step b: 4-Amino-1-(3-methoxypropyl)piperidine

[0801] 4-Amino 1-(3-methoxypropyl)piperidine is prepared from4-carboxamide-1-(3-methoxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0802] Method 2

[0803] Scheme C, Step a: 1-(3-Methoxypropyl)-4-piperidone

[0804] 1-(3-Methoxypropyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-3-methoxypropane essentially as described above in Example38, Scheme C, step a.

[0805] Scheme C, Step b: 1-(3-Methoxypropyl)-4-piperidone Oxime

[0806] 1-(3-Methoxypropyl)-4-piperidone oxime is prepared from1-(3-methoxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0807] Scheme C, Step c: 4-Amino-1-(3-methoxypropyl)piperidine

[0808] 4-Amino-1-(3-methoxypropyl)piperidine is prepared from1-(3-methoxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0809] Scheme A, Step b:2-Chloro-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0810]2-Chloro-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-methoxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0811] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0812]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-methoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 642-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0813] Preparation of 4-Amino-1-(3-ethoxypropyl)piperidine

[0814] Method 1

[0815] Scheme B, Step a: 4-Carboxamide-1-(3-ethoxypropyl)piperidine

[0816] 4-Carboxamide-1-(3-ethoxypropyl)piperidine may be prepared fromisonipecotamide and 1-chloro-3-ethoxypropane essentially as describedabove in Example 38, Scheme B, step a.

[0817] Scheme B, Step b: 4-Amino-1-(3-ethoxypropyl)piperidine

[0818] 4-Amino-1-(3-ethoxypropyl)piperidine is prepared from4-carboxamide-1-(3-ethoxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0819] Method 2

[0820] Scheme C, Step a: 1-(3-Ethoxypropyl)-4-piperidone

[0821] 1-(3-Ethoxypropyl)-4-piperidone is prepared from 4-piperidone and1-chloro-3-ethoxypropane essentially as described above in Example 38,Scheme C, step a.

[0822] Scheme C, Step b: 1-(3-Ethoxypropyl)-4-piperidone Oxime

[0823] 1-(3-Ethoxypropyl)-4-piperidone oxime is prepared from1-(3-ethoxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0824] Scheme C, Step c: 4-Amino-1-(3-ethoxypropyl)piperidine

[0825] 4-Amino-1-(3-ethoxypropyl)piperidine is prepared from1-(3-ethoxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0826] Scheme A, Step b:2-Chloro-6-[4-(1-(3-ethoxypropyl)piperidinylamino]-9-cyclopentylpurine

[0827]2-Chloro-6-[4-(1-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-ethoxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0828] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0829]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-ethoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 652-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0830] Preparation of 4-Amino-1-(3-propoxypropyl)piperidine

[0831] Method 1

[0832] Scheme B, Step a: 4-Carboxamide-1-(3-propoxypropyl)piperidine

[0833] 4-Carboxamide-1-(3-propoxypropyl)piperidine may be prepared fromisonipecotamide and 1-chloro-3-propoxypropane essentially as describedabove in Example 38, Scheme B, step a.

[0834] Scheme B, Step b: 4-Amino-1-(3-propoxypropyl)piperidine

[0835] 4-Amino-1-(3-propoxypropyl)piperidine is prepared from4-carboxamide-1-(3-propoxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0836] Method 2

[0837] Scheme C, Step a: 1-(3-Propoxypropyl)-4-piperidone

[0838] 1-(3-Propoxypropyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-3-propoxypropane essentially as described above in Example38, Scheme C, step a.

[0839] Scheme C, Step b: 1-(3-Propoxypropyl)-4-piperidone Oxime

[0840] 1-(3-Propoxypropyl)-4-piperidone oxime is prepared from1-(3-propoxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0841] Scheme C, Step c: 4-Amino-1-(3-propoxypropyl)piperidine

[0842] 4-Amino-1-(3-propoxypropyl)piperidine is prepared from1-(3-propoxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0843] Scheme A, Step b:2-Chloro-6-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0844]2-Chloro-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-propoxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0845] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0846]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-propoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 662-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0847] Preparation of 4-Amino-1-(3-butoxypropyl)piperidine

[0848] Method 1

[0849] Scheme B, Step a: 4-Carboxamide-1-(3-butoxypropyl)piperidine

[0850] 4-Carboxamide-1-(3-butoxypropyl)piperidine may be prepared fromisonipecotamide and 1-chloro-3-butoxypropane essentially as describedabove in Example 38, Scheme B, step a.

[0851] Scheme B, Step b: 4-Amino-1-(3-butoxypropyl)piperidine

[0852] 4-Amino-1-(3-butoxypropyl)piperidine is prepared from4-carboxamide-1-(3-butoxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0853] Method 2

[0854] Scheme C, Step a: 1-(3-Butoxypropyl)-4-piperidone

[0855] 1-(3-Butoxypropyl)-4-piperidone is prepared from 4-piperidone and1-chloro-3-butoxypropane essentially as described above in Example 38,Scheme C, step a.

[0856] Scheme C, Step b: 1-(3-Butoxypropyl)-4-piperidone Oxime

[0857] 1-(3-Butoxypropyl)-4-piperidone oxime is prepared from1-(3-butoxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0858] Scheme C, Step c: 4-Amino-1-(3-butoxypropyl)piperidine

[0859] 4-Amino-1-(3-butoxypropyl)piperidine is prepared from1-(3-butoxypropyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0860] Scheme A, Step b:2-Chloro-6-[4-(1-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0861]2-Chloro-6-[4-(1-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-butoxypropyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0862] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(1-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0863]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-butoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-butoxypropyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 67

[0864]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0865] Preparation of 4-Amino-1-(3-benzyloxypropyl)piperidine

[0866] Method 1

[0867] Scheme B, Step a: 4-Carboxamide-1-(3-benzyloxypropyl)piperidine

[0868] 4-Carboxamide-1-(3-benzyloxypropyl)piperidine may be preparedfrom isonipecotamide and 1-chloro-3-benzyloxypropane essentially asdescribed above in Example 38, Scheme B, step a.

[0869] Scheme B, Step b: 4-Amino-1-(3-benzylpropyl)piperidine

[0870] 4-Amino-1-(3-benzyloxypropyl)piperidine is prepared from4-carboxamide-1-(3-benzyloxypropyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0871] Method 2

[0872] Scheme C, Step a: 1-(3-Benyloxypropyl)-4-piperidone

[0873] 1-(3-Benzyloxypropyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-3-benzyloxypropane essentially as described above inExample 38, Scheme C, step a.

[0874] Scheme C, Step b: 1-(3-Benzyloxypropyl)-4-piperidone Oxime

[0875] 1-(3-Benzyloxypropyl)-4-piperidone oxime is prepared from1-(3-benzyloxypropyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0876] Scheme C, Step c: 4-Amino-1-(3-benzyloxypropyl)piperidine

[0877] 4-Amino-1-(3-benzyloxypropyl)piperidine is prepared from1-(3-benzyloxypropyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[0878] Scheme A, Step b:2-Chloro-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0879]2-Chloro-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-benzyloxypropyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[0880] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0881]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-benzyloxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 682-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0882] Preparation of4-Amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine

[0883] Method 1

[0884] Scheme B, Step a:4-Carboxamide-1-(3-(2-phenylethyleneoxy)propyl)piperidine

[0885] 4-Carboxamide-1-(3-(2-phenylethyleneoxy)propyl)piperidine may beprepared from isonipecotamide and1-chloro-3-(2-phenylethyleneoxy)propane essentially as described abovein Example 38, Scheme B, step a.

[0886] Scheme B, Step b:4-Amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine

[0887] 4-Amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine is preparedfrom 4-carboxamide-1-(3-(2-phenylethyleneoxy)propyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[0888] Method 2

[0889] Scheme C, Step a: 1-(3-(2-Phenylethyleneoxy)-4-piperidone

[0890] 1-(3-(2-Phenylethyleneoxy)-4-piperidone is prepared from4-piperidone and 1-chloro-3-(2-phenylethyleneoxy)propane essentially asdescribed above in Example 38, Scheme C, step a.

[0891] Scheme C, Step b: 1-(3-(2-Phenylethyleneoxy)-piperidone Oxime

[0892] 1-(3-(2-Phenylethyleneoxy)-4-piperidone oxime is prepared from1-(3-(2-phenylethyleneoxy)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0893] Scheme C, Step c:4-Amino-1-(3-(2-phenylethyleneoxy)proyl)piperidine

[0894] 4-Amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine is preparedfrom 1-(3-(2-phenylethyleneoxy)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[0895] Scheme A, Step b:2-Chloro-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0896]2-Chloro-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-(2-phenylethyleneoxy)propyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0897] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0898]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-(2-phenylethyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 692-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0899] Preparation of4-Amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine

[0900] Method 1

[0901] Scheme B, Step a:4-Carboxamide-1-(3-(3-phenylpropyleneoxy)propyl)piperidine

[0902] 4-Carboxamide-1-(3-(3-phenylpropyleneoxy)propyl)piperidine may beprepared from isonipecotamide and1-chloro-3-(3-phenylpropyleneoxy)propane essentially as described abovein Example 38, Scheme B, step a.

[0903] Scheme B, Step b:4-Amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine

[0904] 4-Amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine is preparedfrom 4-carboxamide-1-(3-(3-phenylpropyleneoxy)propyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[0905] Method 2

[0906] Scheme C, Step a: 1-(3-(3-Phenylpropyleneoxy)propyl)-4-piperidone

[0907] 1-(3-(3-Phenylpropyleneoxy)propyl)-4-piperidone is prepared from4-piperidone and 1-chloro-3-(3-phenylpropyleneoxy)propane essentially asdescribed above in Example 38, Scheme C, step a.

[0908] Scheme C, Step b: 1-(3-(3-Phenylpropyleneoxy)propyl)-4-piperidoneOxime

[0909] 1-(3-(3-Phenylpropyleneoxy)propyl)-4-piperidone oxime is preparedfrom 1-(3-(3-phenylpropyleneoxy)propyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[0910] Scheme C, Step c:4-Amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine

[0911] 4-Amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine is preparedfrom 1-(3-(3-phenylpropyleneoxy)propyl)-4-piperidone oxime essentiallyas described above in Example 38, Scheme C, step c.

[0912] Scheme A, Step b:2-Chloro-6-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0913]2-Chloro-6-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-(3-phenylpropyleneoxy)propyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0914] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0915]2-[Trans-(4-aminocyclohexyl)amino]-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-(3-phenylpropyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 702-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0916] Preparation of4-Amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine

[0917] Method 1

[0918] Scheme B, Step a:4-Carboxamide-1-(3-(4-phenylbutyleneoxy)propyl)piperidine

[0919] 4-Carboxamide-1-(3-(4-phenylbutyleneoxy)propyl)piperidine may beprepared from isonipecotamide and1-chloro-3-(4-phenylbutyleneoxy)propane essentially as described abovein Example 38, Scheme B, step a.

[0920] Scheme B, Step b:4-Amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine

[0921] 4-Amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine is preparedfrom 4-carboxamide-1-(3-(4-phenylbutyleneoxy)propyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[0922] Method 2

[0923] Scheme C, Step a: 1-(3-(4-Phenylbutyleneoxy)propyl)-4-piperidone

[0924] 1-(3-(4-Phenylbutyleneoxy)propyl)-4-piperidone is prepared from4-piperidone and 1-chloro-3-(4-phenylbutyleneoxy)propane essentially asdescribed above in Example 38, Scheme C, step a.

[0925] Scheme C, Step b: 1-(3-(4-Phenylbutyleneoxy)propyl)-4-piperidoneOxime

[0926] 1-(3-(4-Phenylbutyleneoxy)propyl)-4-piperidone oxime is preparedfrom 1-(3-(4-phenylbutyleneoxy)propyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[0927] Scheme C, Step c:4-Amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine

[0928] 4-Amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine is preparedfrom 1-(3-(4-phenylbutyleneoxy)propyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[0929] Scheme A, Step b:2-Chloro-6-[4-(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0930]2-Chloro-6-[4-(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-(4-phenylbutyleneoxy)propyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[0931] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurine

[0932]2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-(4-phenylbutyleneoxy)propyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 712-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0933] Preparation of 4-Amino-1-(4-hydroxybutyl)piperidine

[0934] Method 1

[0935] Scheme B, Step a: 4-Carboxamide-1-(4-hydroxybutyl)piperidine

[0936] 4-Carboxamide-1-(4-hydroxybutyl)piperidine may be prepared fromisonipecotamide and 4-chloro-1-butanol essentially as described above inExample 38, Scheme B, step a.

[0937] Scheme B, Step b: 4-Amino-1-(hydroxybutyl)piperidine

[0938] 4-Amino-1-(4-hydroxybutyl)piperidine is prepared from4-carboxamide-1-(4-hydroxybutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0939] Method 2

[0940] Scheme C, Step a: 1-(4-Hydroxybutyl)-4-piperidone

[0941] 1-(4-Hydroxybutyl)-4-piperidone is prepared from 4-piperidone and4-chloro-1-butanol essentially as described above in Example 38, SchemeC, step a.

[0942] Scheme C, Step b: 1-(4-Hydroxybutyl)-4-piperidone Oxime

[0943] 1-(4-Hydroxybutyl)-4-piperidone oxime is prepared from1-(4-hydroxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0944] Scheme C, Step c: 4-Amino-1-(4-hydroxybutyl)piperidine

[0945] 4-Amino-1-(4-hydroxybutyl)piperidine is prepared from1-(4-hydroxybutyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0946] Scheme A, Step b:2-Chloro-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0947]2-Chloro-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-hydroxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0948] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0949]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-hydroxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 722-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0950] Preparation of 4-Amino-1-(4-methoxybutyl)piperidine

[0951] Method 1

[0952] Scheme B, Step a: 4-Carboxamide-1-(4-methoxybutyl)piperidine

[0953] 4-Carboxamide-1-(4-methoxybutyl)piperidine may be prepared fromisonipecotamide and 1-chloro-4-methoxybutane essentially as describedabove in Example 38, Scheme B, step a.

[0954] Scheme B, Step b: 4-Amino-1-(4-methoxybutyl)piperidine

[0955] 4-Amino-1-(4-methoxybutyl)piperidine is prepared from4-carboxamide-1-(4-methoxybutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0956] Method 2

[0957] Scheme C, Step a: 1-(4-Methoxybutyl)-4-piperidone

[0958] 1-(4-Methoxybutyl)-4-piperidone is prepared from 4-piperidone and1-chloro-4-methoxybutane essentially as described above in Example 38,Scheme C, step a.

[0959] Scheme C, Step b: 1-(4-Methoxybutyl)piperidone Oxime

[0960] 1-(4-Methoxybutyl)-4-piperidone oxime is prepared from1-(4-methoxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0961] Scheme C, Step c: 4-Amino-1-(4-methoxybutyl)piperidine

[0962] 4-Amino-1-(4-methoxybutyl)piperidine is prepared from1-(4-methoxybutyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0963] Scheme A, Step b:2-Chloro-6-[4-(1-(4-methoxybutyl)piperidinylamino]-9-cyclopentylpurine

[0964]2-Chloro-6-[4-(1-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-methoxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0965] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0966]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-methoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 732-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0967] Preparation of 4-Amino-1-(4-ethoxybutyl)piperidine

[0968] Method 1

[0969] Scheme B, Step a: 4-Carboxamide-1-(4-ethoxybutyl)piperidine

[0970] 4-Carboxamide-1-(4-ethoxybutyl)piperidine may be prepared fromisonipecotamide and 1-chloro-4-ethoxybutane essentially as describedabove in Example 38, Scheme B, step a.

[0971] Scheme B, Step b: 4-Amino-1-(4-ethoxybutyl)piperidine

[0972] 4-Amino-1-(4-ethoxybutyl)piperidine is prepared from4-carboxamide-1-(4-ethoxybutyl)piperidine essentially as described abovein Example 38, Scheme B, step b.

[0973] Method 2

[0974] Scheme C, Step a: 1-(4-Ethoxybutyl)-4-piperidone

[0975] 1-(4-Ethoxybutyl)-4-piperidone is prepared from 4-piperidone and1-chloro-4-ethoxybutane essentially as described above in Example 38,Scheme C, step a.

[0976] Scheme C, Step b: 1-(4-Ethoxybutyl)-4-piperidone Oxime

[0977] 1-(4-Ethoxybutyl)-4-piperidone oxime is prepared from1-(4-ethoxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0978] Scheme C, Step c: 4-Amino-1-(4-ethoxybutyl)piperidine

[0979] 4-Amino-1-(4-ethoxybutyl)piperidine is prepared from1-(4-ethoxybutyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0980] Scheme A, Step b:2-Chloro-6-[4-(1-(4-ethoxybutyl)piperidinylamino]-9-cyclopentylpurine

[0981]2-Chloro-6-[4-(1-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-ethoxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0982] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0983]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-ethoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 742-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0984] Preparation of 4-Amino-1-(4-propoxybutyl)piperidine

[0985] Method 1

[0986] Scheme B, Step a: 4-Carboxamide-1-(4-propoxybutyl)piperidine

[0987] 4-Carboxamide-1-(4-propoxybutyl)piperidine may be prepared fromisonipecotamide and 1-chloro-4-propoxybutane essentially as describedabove in Example 38, Scheme B, step a.

[0988] Scheme B, Step b: 4-Amino-1-(4-propoxybutyl)piperidine

[0989] 4-Amino-1-(4-propoxybutyl)piperidine is prepared from4-carboxamide-1-(4-propoxybutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[0990] Method 2

[0991] Scheme C, Step a: 1-(4-Propoxybutyl)-4-piperidone

[0992] 1-(4-Propoxybutyl)-4-piperidone is prepared from 4-piperidone and1-chloro-4-propoxybutane essentially as described above in Example 38,Scheme C, step a.

[0993] Scheme C, Step b: 1-(4-Propoxybutyl)-4-piperidone Oxime

[0994] 1-(4-Propoxybutyl)-4-piperidone oxime is prepared from1-(4-propoxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[0995] Scheme C, Step c: 4-Amino-1-(4-propoxybutyl)piperidine

[0996] 4-Amino-1-(4-propoxybutyl)piperidine is prepared from1-(4-propoxybutyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[0997] Scheme A, Step b:2-Chloro-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[0998]2-Chloro-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-propoxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[0999] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1000]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-propoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 752-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1001] Preparation of 4-Amino-1-(4-butoxybutyl)piperidine

[1002] Method 1

[1003] Scheme B, Step a: 4-Carboxamide-1-(4-butoxybutyl)piperidine

[1004] 4-Carboxamide-1-(4-butoxybutyl)piperidine may be prepared fromisonipecotamide and 1-chloro-4-butoxybutane essentially as describedabove in Example 38, Scheme B, step a.

[1005] Scheme B, Step b: 4-Amino-1-(4-butoxybutyl)piperidine

[1006] 4-Amino-1-(4-butoxybutyl)piperidine is prepared from4-carboxamide-1-(4-butoxybutyl)piperidine essentially as described abovein Example 38, Scheme B, step b.

[1007] Method 2

[1008] Scheme C, Step a: 1-(4-Butoxybutyl)-4-piperidone

[1009] 1-(4-Butoxybutyl)-4-piperidone is prepared from 4-piperidone and1-chloro-4-butoxybutane essentially as described above in Example 38,Scheme C, step a.

[1010] Scheme C, Step b: 1-(4-Butoxybutyl)-4-piperidone Oxime

[1011] 1-(4-Butoxybutyl)-4-piperidone oxime is prepared from1-(4-butoxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1012] Scheme C, Step c: 4-Amino-1-(4-butoxybutyl)piperidine

[1013] 4-Amino-1-(4-butoxybutyl)piperidine is prepared from1-(4-butoxybutyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1014] Scheme A, Step b:2-Chloro-6-[4-(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1015]2-Chloro-6-[4-(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-butoxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1016] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1017]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-butoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 762-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1018] Preparation of 4-Amino-1-(4-benzyloxybutyl)piperidine

[1019] Method 1

[1020] Scheme B, Step a: 4-Carboxamide-1-(4-benzyloxybutyl)piperidine

[1021] 4-Carboxamide-1-(4-benzyloxybutyl)piperidine may be prepared fromisonipecotamide and 1-chloro-4-benzyloxybutane essentially as describedabove in Example 38, Scheme B, step a.

[1022] Scheme B, Step b: 4-Amino-1-(4-benzyloxybutyl)piperidine

[1023] 4-Amino-1-(4-benzyloxybutyl)piperidine is prepared from4-carboxamide-1-(4-benzyloxybutyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1024] Method 2

[1025] Scheme C, Step a: 1-(4-Benzyloxybutyl)-4-piperidone

[1026] 1-(4-Benzyloxybutyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-4-benzyloxybutane essentially as described above in Example38, Scheme C, step a.

[1027] Scheme C, Step b: 1-(4-Benzyloxybutyl)-4-piperidone Oxime

[1028] 1-(4-Benzyloxybutyl)-4-piperidone oxime is prepared from1-(4-benzyloxybutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1029] Scheme C, Step c: 4-Amino-1-(4-benzyloxybutyl)piperidine

[1030] 4-Amino-1-(4-benzyloxybutyl)piperidine is prepared from1-(4-benzyloxybutyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[1031] Scheme A, Step b:2-Chloro-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1032]2-Chloro-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(benzyloxybutyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1033] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1034]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-benzyloxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 772-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1035] Preparation of 4-Amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine

[1036] Method 1

[1037] Scheme B, Step a:4-Carboxamide-1-(4-(2-phenylethyleneoxy)butyl)piperidine

[1038] 4-Carboxamide-1-(4-(2-phenylethyleneoxy)butyl)piperidine may beprepared from isonipecotamide and 1-chloro-4-(2-phenylethyleneoxy)butaneessentially as described above in Example 38, Scheme B, step a.

[1039] Scheme B, Step b:4-Amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine

[1040] 4-Amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine is preparedfrom 4-carboxamide-1-(4-(2-phenylethyleneoxy)butyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1041] Method 2

[1042] Scheme C, Step a: 1-(4-(2-Phenylethyleneoxy)butyl)-4-piperidone

[1043] 1-(4-(2-Phenylethyleneoxy)butyl)-4-piperidone is prepared from4-piperidone and 1-chloro-4-(2-phenylethyleneoxy)butane essentially asdescribed above in Example 38, Scheme C, step a.

[1044] Scheme C, Step b: 1-(4-(2-Phenylethyleneoxy)butyl)-4-piperidoneOxime

[1045] 1-(4-(2-Phenylethyleneoxy)butyl)-4-piperidone oxime is preparedfrom 1-(4-(2-phenylethyleneoxy)butyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1046] Scheme C, Step c:4-Amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine

[1047] 4-Amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine is preparedfrom 1-(4-(2-phenylethyleneoxy)butyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1048] Scheme A, Step b:2-Chloro-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1049]2-Chloro-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-(2-phenylethyleneoxy)butyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1050] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1051]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-(2-phenylethyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 782-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1052] Preparation of4-Amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine

[1053] Method 1

[1054] Scheme B, Step a:4-Carboxamide-1-(4-(3-phenylpropyleneoxy)butyl)piperidine

[1055] 4-Carboxamide-1-(4-(3-phenylpropyleneoxy)butyl)piperidine may beprepared from isonipecotamide and1-chloro-(4-(3-phenylpropyleneoxy)butane essentially as described abovein Example 38, Scheme B, step a.

[1056] Scheme B, Step b:4-Amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine

[1057] 4-Amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine is preparedfrom 4-carboxamide-1-(4-(3-phenylpropyleneoxy)butyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1058] Method 2

[1059] Scheme C, Step a: 1-(4-(3-Phenylpropyleneoxy)butyl)-4-piperidone

[1060] 1-(4-(3-Phenylpropyleneoxy)butyl)-4-piperidone is prepared from4-piperidone and 1-chloro-(4-(3-phenylpropyleneoxy)butane essentially asdescribed above in Example 38, Scheme C, step a.

[1061] Scheme C, Step b: 1-(4-(3-Phenylpropyleneoxy)butyl)-4-piperidoneOxime

[1062] 1-(4-(3-Phenylpropyleneoxy)butyl)-4-piperidone oxime is preparedfrom 1-(4-(3-phenylpropyleneoxy)butyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1063] Scheme C, Step c:4-Amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine

[1064] 4-Amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine is preparedfrom 1-(4-(3-phenylpropyleneoxy)butyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1065] Scheme A, Step b:2-Chloro-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1066]2-Chloro-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-(3-phenylpropyleneoxy)butyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1067] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1068]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-(3-phenylpropyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 792-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1069] Preparation of 4-Amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine

[1070] Method 1

[1071] Scheme B, Step a:4-Carboxamide-1-(4-(4-phenylbutyleneoxy)butyl)piperidine

[1072] 4-Carboxamide-1-(4-(4-phenylbutyleneoxy)butyl)piperidine may beprepared from isonipecotamide and 1-chloro-4-(4-phenylbutyleneoxy)butaneessentially as described above in Example 38, Scheme B, step a.

[1073] Scheme B, Step b:4-Amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine

[1074] 4-Amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine is preparedfrom 4-carboxamide-1-(4-(4-phenylbutyleneoxy)butyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1075] Method 2

[1076] Scheme C, Step a: 1-(4-(4-Phenylbutyleneoxy)butyl)-4-piperidone

[1077] 1-(4-(4-Phenylbutyleneoxy)butyl)-4-piperidone is prepared from4-piperidone and 1-chloro-4-(4-phenylbutyleneoxy)butane essentially asdescribed above in Example 38, Scheme C, step a.

[1078] Scheme C, Step b: 1-(4-(4-Phenylbutyleneoxy)butyl)-4-piperidoneOxime

[1079] 1-(4-(4-Phenylbutyleneoxy)butyl)-4-piperidone oxime is preparedfrom 1-(4-(4-phenylbutyleneoxy)butyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1080] Scheme C, Step c:4-Amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine

[1081] 4-Amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine is preparedfrom 1-(4-(4-phenylbutyleneoxy)butyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1082] Scheme A, Step b:2-Chloro-6-[4-(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1083]2-Chloro-6-[4-(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-(4-phenylbutyleneoxy)butyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1084] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurine

[1085]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[(1-(4-(4-phenylbutyleneoxy)butyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 802-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-hydroxypentyl)piperidinylamino]-9-cyclopentylpurine

[1086] Preparation of 4-Amino-1-(5-hydroxypentyl)piperidine

[1087] Method 1

[1088] Scheme B, Step a: 4-Carboxamide-1-(5-hydroxypentyl)piperidine

[1089] 4-Carboxamide-1-(5-hydroxypentyl)piperidine may be prepared fromisonipecotamide and 1-chloro-5-hydroxypentane essentially as describedabove in Example 38, Scheme B, step a.

[1090] Scheme B, Step b: 4-Amino-1-(5-hydroxypentyl)piperidine

[1091] 4-Amino-1-(5-hydroxypentyl)piperidine is prepared from4-carboxamide-1-(5-hydroxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1092] Method 2

[1093] Scheme C, Step a: 1-(5-Hydroxypentyl)-4-piperidone

[1094] 1-(5-Hydroxypentyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-5-hydroxypentane essentially as described above in Example38, Scheme C, step a.

[1095] Scheme C, Step b: 1-(5-Hydroxypentyl)-4-piperidone Oxime

[1096] 1-(5-Hydroxypentyl)-4-piperidone oxime is prepared from1-(5-hydroxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1097] Scheme C, Step c: 4-Amino-1-(5-hydroxypentyl)piperidine

[1098] 4-Amino-1-(5-hydroxypentyl)piperidine is prepared from1-(5-hydroxypentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1099] Scheme A, Step b:2-Chloro-6-[4-(1-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurine

[1100]2-Chloro-6-[4-(1-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-hydroxypentyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1101] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-hydroxypentyl)piperidinylamino]-9-cyclopentylpurine

[1102]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-hydroxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 812-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-methoxypentyl)piperidinylamino]-9-cyclopentylpurine

[1103] Preparation of 4-Amino-(5-methoxypentyl)piperidine

[1104] Method 1

[1105] Scheme B, Step a: 4-Carboxamide-1-(5-methoxypentyl)piperidine

[1106] 4-Carboxamide-1-(5-methoxypentyl)piperidine may be prepared fromisonipecotamide and 1-chloro-5-methoxypentane essentially as describedabove in Example 38, Scheme B, step a.

[1107] Scheme B, Step b: 4-Amino-(5-methoxypentyl)piperidine

[1108] 4-Amino-(5-methoxypentyl)piperidine is prepared from4-carboxamide-1-(5-methoxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1109] Method 2

[1110] Scheme C, Step a: 1-(5-Methoxypentyl)-4-piperidone

[1111] 1-(5-Methoxypentyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-5-methoxypentane essentially as described above in Example38, Scheme C, step a.

[1112] Scheme C, Step b: 1-(5-Methoxypentyl)-4-piperidone Oxime

[1113] 1-(5-Methoxypentyl)-4-piperidone oxime is prepared from1-(5-methoxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1114] Scheme C, Step c: 4-Amino-(5-methoxypentyl)piperidine

[1115] 4-Amino-(5-methoxypentyl)piperidine is prepared from1-(5-methoxypentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1116] Scheme A, Step b:2-Chloro-6-[4-(1-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1117]2-Chloro-6-[4-(1-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-(5-methoxypentyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1118] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1119]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-methoxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 822-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1120] Preparation of 4-Amino-1-(5-ethoxypentyl)piperidine

[1121] Method 1

[1122] Scheme B, Step a: 4-Carboxamide-1-(5-ethoxypentyl)piperidine

[1123] 4-Carboxamide-1-(5-ethoxypentyl)piperidine may be prepared fromisonipecotamide and 1-chloro-5-ethoxypentane essentially as describedabove in Example 38, Scheme B, step a.

[1124] Scheme B, Step b: 4-Amino-1-(5-ethoxypentyl)piperidine

[1125] 4-Amino-1-(5-ethoxypentyl)piperidine is prepared from4-carboxamide-1-(5-ethoxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1126] Method 2

[1127] Scheme C, Step a: 1-(5-Ethoxypentyl)-4-piperidone

[1128] 1-(5-Ethoxypentyl)-4-piperidone is prepared from 4-piperidone and1-chloro-5-ethoxypentane essentially as described above in Example 38,Scheme C, step a.

[1129] Scheme C, Step b: 1-(5-Ethoxypentyl)-4-piperidone Oxime

[1130] 1-(5-Ethoxypentyl)-4-piperidone oxime is prepared from1-(5-ethoxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1131] Scheme C, Step c: 4-Amino-1-(5-ethoxypentyl)piperidine

[1132] 4-Amino-1-(5-ethoxypentyl)piperidine is prepared from1-(5-ethoxypentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1133] Scheme A, Step b:2-Chloro-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1134]2-Chloro-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-ethoxypentyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1135] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1136]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-ethoxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 832-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-propoxypentyl)piperidinylamino]-9-cyclopentylpurine

[1137] Preparation of 4-Amino-1-(5-propoxypentyl)piperidine

[1138] Method 1

[1139] Scheme B, Step a: 4-Carboxamide-1-(5-propoxypentyl)piperidine

[1140] 4-Carboxamide-1-(5-propoxypentyl)piperidine may be prepared fromisonipecotamide and 1-chloro-5-propoxypentane essentially as describedabove in Example 38, Scheme B, step a.

[1141] Scheme B, Step b: 4-Amino-1-(5-propoxypentyl)piperidine

[1142] 4-Amino-1-(5-propoxypentyl)piperidine is prepared from4-carboxamide-1-(5-propoxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1143] Method 2

[1144] Scheme C, Step a: 1-(5-Propoxypentyl)-4-piperidone

[1145] 1-(5-Propoxypentyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-5-propoxypentane essentially as described above in Example38, Scheme C, step a.

[1146] Scheme C, Step b: 1-(5-Propoxypentyl)-4-piperidone Oxime

[1147] 1-(5-Propoxypentyl)-4-piperidone oxime is prepared from1-(5-propoxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1148] Scheme C, Step c: 4-Amino-1-(5-propoxypentyl)piperidine

[1149] 4-Amino-1-(5-propoxypentyl)piperidine is prepared from1-(5-propoxypentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1150] Scheme A, Step b:2-Chloro-6-[4-(1-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1151]2-Chloro-6-[4-(1-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-propoxypentyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1152] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1153]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-propoxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 842-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurine

[1154] Preparation of 4-Amino-1-(5-butoxypentyl)piperidine

[1155] Method 1

[1156] Scheme B, Step a: 4-Carboxamide-1-(5-butoxypentyl)piperidine

[1157] 4-Carboxamide-1-(5-butoxypentyl)piperidine may be prepared fromisonipecotamide and 1-chloro-5-butoxypentane essentially as describedabove in Example 38, Scheme B, step a.

[1158] Scheme B, Step b: 4-Amino-1-(5-butoxypentyl)piperidine

[1159] 4-Amino-1-(5-butoxypentyl)piperidine is prepared from4-carboxamide-1-(5-butoxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1160] Method 2

[1161] Scheme C, Step a: 1-(5-Butoxypentyl)-4-piperidone

[1162] 1-(5-Butoxypentyl)-4-piperidone is prepared from 4-piperidone and1-chloro-5-butoxypentane essentially as described above in Example 38,Scheme C, step a.

[1163] Scheme C, Step b: 1-(5-Butoxypentyl)-4-piperidone Oxime

[1164] 1-(5-Butoxypentyl)-4-piperidone oxime is prepared from1-(5-butoxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1165] Scheme C, Step c: 4-Amino-1-(5-butoxypentyl)piperidine

[1166] 4-Amino-1-(5-butoxypentyl)piperidine is prepared from1-(5-butoxypentyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1167] Scheme A, Step b:2-Chloro-6-[4-(1-(5-butoxypentyl)piperidinylamino]-9-cyclopentylpurine

[1168]2-Chloro-6-[4-(1-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-butoxypentyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1169] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[1-(5-butoxypentyl)piperidinylamino]-9-cyclopentylpurine

[1170]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-butoxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 852-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurine

[1171] Preparation of 4-Amino-1-(5-benzyloxypentyl)piperidine

[1172] Method 1

[1173] Scheme B, Step a: 4-Carboxamide-1-(5-benzyloxypentyl)piperidine

[1174] 4-Carboxamide-1-(5-benzyloxypentyl)piperidine may be preparedfrom isonipecotamide and 1-chloro-5-benzyloxypentane essentially asdescribed above in Example 38, Scheme B, step a.

[1175] Scheme B, Step b: 4-Amino-1-(5-benzyloxypentyl)piperidine

[1176] 4-Amino-1-(5-benzyloxypentyl)piperidine is prepared from4-carboxamide-1-(5-benzyloxypentyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1177] Method 2

[1178] Scheme C, Step a: 1-(5-Benzyloxypentyl)-4-piperidone

[1179] 1-(5-Benzyloxypentyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-5-benzyloxypentane essentially as described above inExample 38, Scheme C, step a.

[1180] Scheme C, Step b: 1-(5-Benzyloxypentyl)-4-piperidone Oxime

[1181] 1-(5-Benzyloxypentyl)-4-piperidone oxime is prepared from1-(5-benzyloxypentyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1182] Scheme C, Step c: 4-Amino-1-(5-benzyloxypentyl)piperidine

[1183] 4-Amino-1-(5-benzyloxypentyl)piperidine is prepared from1-(5-benzyloxypentyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[1184] Scheme A, Step b:2-Chloro-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurine

[1185]2-Chloro-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-benzyloxypentyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[1186] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurine

[1187]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-benzyloxypentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 862-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1188] Preparation of4-Amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine

[1189] Method 1

[1190] Scheme B, Step a:4-Carboxamide-1-(5-(2-phenylethyleneoxy)pentyl)piperidine

[1191] 4-Carboxamide-1-(5-(2-phenylethyleneoxy)pentyl)piperidine may beprepared from isonipecotamide and1-chloro-5-(2-phenylethyleneoxy)pentane essentially as described abovein Example 38, Scheme B, step a.

[1192] Scheme B, Step b:4-Amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine

[1193] 4-Amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine is preparedfrom 4-carboxamide-1-(5-(2-phenylethyleneoxy)pentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1194] Method 2

[1195] Scheme C, Step a: 1-(5-(2-Phenylethyleneoxy)pentyl)-4-piperidone

[1196] 1-(5-(2-Phenylethyleneoxy)pentyl)-4-piperidone is prepared from4-piperidone and 1-chloro-5-(2-phenylethyleneoxy)pentane essentially asdescribed above in Example 38, Scheme C, step a.

[1197] Scheme C, Step b: 1-(5-(2-Phenylethyleneoxy)pentyl)-4-piperidoneOxime

[1198] 1-(5-(2-Phenylethyleneoxy)pentyl)-4-piperidone oxime is preparedfrom 1-(5-(2-phenylethyleneoxy)pentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1199] Scheme C, Step c:4-Amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine

[1200] 4-Amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine is preparedfrom 1-(5-(2-phenylethyleneoxy)pentyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1201] Scheme A, Step b:2-Chloro-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1202]2-Chloro-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-(2-phenylethyleneoxy)pentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1203] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1204]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-(2-phenylethyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 872-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1205] Preparation of4-Amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine

[1206] Method 1

[1207] Scheme B, Step a:4-Carboxamide-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine

[1208] 4-Carboxamide-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine may beprepared from isonipecotamide and1-chloro-5-(3-phenylpropyleneoxy)pentane essentially as described abovein Example 38, Scheme B, step a.

[1209] Scheme B, Step b:4-Amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine

[1210] 4-Amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine is preparedfrom 4-carboxamide-1-(5-(3-phenylpropyleneoxy)pentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1211] Method 2

[1212] Scheme C, Step a: 1-(5-(3-Phenylpropyleneoxy)pentyl)-4-piperidone

[1213] 1-(5-(3-Phenylpropyleneoxy)pentyl)-4-piperidone is prepared from4-piperidone and 1-chloro-5-(3-phenylpropyleneoxy)pentane essentially asdescribed above in Example 38, Scheme C, step a.

[1214] Scheme C, Step b: 1-(5-(3-Phenylpropyleneoxy)pentyl)-4-piperidoneOxime

[1215] 1-(5-(3-Phenylpropyleneoxy)pentyl)-4-piperidone oxime is preparedfrom 1-(5-(3-phenylpropyleneoxy)pentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1216] Scheme C, Step c:4-Amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine

[1217] 4-Amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine is preparedfrom 1-(5-(3-phenylpropyleneoxy)pentyl)-4-piperidone oxime essentiallyas described above in Example 38, Scheme C, step c.

[1218] Scheme A, Step b:2-Chloro-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1219]2-Chloro-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-(3-phenylpropyleneoxy)pentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1220] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1221]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-(3-phenylpropyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 882-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1222] Preparation of4-Amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine

[1223] Method 1

[1224] Scheme B, Step a:4-Carboxamide-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine

[1225] 4-Carboxamide-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine may beprepared from isonipecotamide and1-chloro-5-(4-phenylbutyleneoxy)pentane essentially as described abovein Example 38, Scheme B, step a.

[1226] Scheme B, Step b:4-Amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine

[1227] 4-Amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine is preparedfrom 4-carboxamide-1-(5-(4-phenylbutyleneoxy)pentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1228] Method 2

[1229] Scheme C, Step a: 1-(5-(4-Phenylbutyleneoxy)pentyl)-4-piperidone

[1230] 1-(5-(4-Phenylbutyleneoxy)pentyl)-4-piperidone is prepared from4-piperidone and 1-chloro-5-(4-phenylbutyleneoxy)pentane essentially asdescribed above in Example 38, Scheme C, step a.

[1231] Scheme C, Step b: 1-(5-(4-Phenylbutyleneoxy)pentyl)-4-piperidoneOxime

[1232] 1-(5-(4-Phenylbutyleneoxy)pentyl)-4-piperidone oxime is preparedfrom 1-(5-(4-phenylbutyleneoxy)pentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1233] Scheme C, Step c:4-Amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine

[1234] 4-Amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine is preparedfrom 1-(5-(4-phenylbutyleneoxy)pentyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1235] Scheme A, Step b:2-Chloro-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1236]2-Chloro-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-(4-phenylbutyleneoxy)pentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1237] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurine

[1238]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-(4-phenylbutyleneoxy)pentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 892-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1239] Preparation of 4-Amino-1-(6-hydroxyhexyl)piperidine

[1240] Method 1

[1241] Scheme B, Step a: 4-Carboxamide-1-(6-hydroxyhexyl)piperidine

[1242] 4-Carboxamide-1-(6-hydroxyhexyl)piperidine may be prepared fromisonipecotamide and 6-chloro-1-hexanol essentially as described above inExample 38, Scheme B, step a.

[1243] Scheme B, Step b: 4-Amino-1-(6-hydroxyhexyl)piperidine

[1244] 4-Amino-1-(6-hydroxyhexyl)piperidine is prepared from4-carboxamide-1-(6-hydroxyhexyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1245] Method 2

[1246] Scheme C, Step a: 1-(6-Hydroxyhexyl)-4-piperidone

[1247] 1-(6-Hydroxyhexyl)-4-piperidone is prepared from 4-piperidone and6-chloro-1-hexanol essentially as described above in Example 38, SchemeC, step a.

[1248] Scheme C, Step b: 1-(6-Hydroxyhexyl)-4-piperidone Oxime

[1249] 1-(6-Hydroxyhexyl)-4-piperidone oxime is prepared from1-(6-hydroxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1250] Scheme C, Step c: 4-Amino-1-(6-hydroxyhexyl)piperidine

[1251] 4-Amino-1-(6-hydroxyhexyl)piperidine is prepared from1-(6-hydroxyhexyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1252] Scheme A, Step b:2-Chloro-6-[4-(1-(6-hydroxyhexyl)piperidinylamino]-9-cyclopentylpurine

[1253]2-Chloro-6-[4-(1-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-hydroxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1254] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1255]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-hydroxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 902-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1256] Preparation of 4-Amino-1-(6-methoxyhexyl)piperidine

[1257] Method 1

[1258] Scheme B, Step a: 4-Carboxamide-1-(6-methoxyhexyl)piperidine

[1259] 4-Carboxamide-1-(6-methoxyhexyl)piperidine may be prepared fromisonipecotamide and 1-chloro-6-methoxyhexane essentially as describedabove in Example 38, Scheme B, step a.

[1260] Scheme B, Step b: 4-Amino-1-(6-methoxyhexyl)piperidine

[1261] 4-Amino-1-(6-methoxyhexyl)piperidine is prepared from4-carboxamide-1-(6-methoxyhexyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1262] Method 2

[1263] Scheme C, Step a: 1-(6-Methoxyhexyl)-4-piperidone

[1264] 1-(6-Methoxyhexyl)-4-piperidone is prepared from 4-piperidone and1-chloro-6-methoxyhexane essentially as described above in Example 38,Scheme C, step a.

[1265] Scheme C, Step b: 1-(6-Methoxyhexyl)-4-piperidone Oxime

[1266] 1-(6-Methoxyhexyl)-4-piperidone oxime is prepared from-(6-methoxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1267] Scheme C, Step c: 4-Amino-1-(6-methoxyhexyl)piperidine

[1268] 4-Amino-1-(6-methoxyhexyl)piperidine is prepared from1-(6-methoxyhexyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1269] Scheme A, Step b:2-Chloro-6-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1270]2-Chloro-6-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-methoxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1271] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1272]2-[Trans-(4-aminocyclohexyl)amino]4-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-methoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 912-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1273] Preparation of 4-Amino-1-(6-ethoxyhexyl)piperidine

[1274] Method 1

[1275] Scheme B, Step a: 4-Carboxamide-1-(6-ethoxyhexyl)piperidine

[1276] 4-Carboxamide-1-(6-ethoxyhexyl)piperidine may be prepared fromisonipecotamide and 1-chloro-6-ethoxyhexane essentially as describedabove in Example 38, Scheme B, step a.

[1277] Scheme B, Step b: 4-Amino-1-(6-ethoxyhexyl)piperidine

[1278] 4-Amino-1-(6-ethoxyhexyl)piperidine is prepared from4-carboxamide-1-(6-ethoxyhexyl)piperidine essentially as described abovein Example 38, Scheme B, step b.

[1279] Method 2

[1280] Scheme C, Step a: 1-(6-Ethoxyhexyl)-4-piperidone

[1281] 1-(6-Ethoxyhexyl)-4-piperidone is prepared from 4-piperidone and1-chloro-6-ethoxyhexane essentially as described above in Example 38,Scheme C, step a.

[1282] Scheme C, Step b: 1-(6-Ethoxyhexyl)-4-piperidone Oxime

[1283] 1-(6-Ethoxyhexyl)-4-piperidone oxime is prepared from1-(6-ethoxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1284] Scheme C, Step c: 4-Amino-1-(6-ethoxyhexyl)piperidine

[1285] 4-Amino-1-(6-ethoxyhexyl)piperidine is prepared from1-(6-ethoxyhexyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1286] Scheme A, Step b:2-Chloro-6-[4-(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1287]2-Chloro-6-[(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-ethoxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1288] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1289]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-ethoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 922-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1290] Preparation of 4-Amino-1-(6-propoxyhexyl)piperidine

[1291] Method 1

[1292] Scheme B, Step a: 4-Carboxamide-1-(6-propoxyhexyl)piperidine

[1293] 4-Carboxamide-1-(6-propoxyhexyl)piperidine may be prepared fromisonipecotamide and 1-chloro-6-propoxyhexane essentially as describedabove in Example 38, Scheme B, step a.

[1294] Scheme B, Step b: 4-Amino-1-(6-propoxyhexyl)piperidine

[1295] 4-Amino-1-(6-propoxyhexyl)piperidine is prepared from4-carboxamide-1-(6-propoxyhexyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1296] Method 2

[1297] Scheme C, Step a: 1-(6-Propoxyhexyl)-4-piperidone

[1298] 1-(6-Propoxyhexyl)-4-piperidone is prepared from 4-piperidone and1-chloro-6-propoxyhexane essentially as described above in Example 38,Scheme C, step a.

[1299] Scheme C, Step b: 1-(6-Propoxyhexyl)-4-piperidone Oxime

[1300] 1-(6-Propoxyhexyl)-4-piperidone oxime is prepared from1-(6-propoxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1301] Scheme C, Step c: 4-Amino-1-(6-propoxyhexyl)piperidine

[1302] 4-Amino-1-(6-propoxyhexyl)piperidine is prepared from1-(6-propoxyhexyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1303] Scheme A, Step b:2-Chloro-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1304]2-Chloro-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-propoxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1305] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1306]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-propoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 932-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1307] Preparation of 4-Amino-1-(6-butoxyhexyl)piperidine

[1308] Method 1

[1309] Scheme B, Step a: 4-Carboxamide-1-(6-butoxyhexyl)piperidine

[1310] 4-Carboxamide-1-(6-butoxyhexyl)piperidine may be prepared fromisonipecotamide and 1-chloro-6-butoxyhexane essentially as describedabove in Example 38, Scheme B, step a.

[1311] Scheme B, Step b: 4-Amino-1-(6-butoxyhexyl)piperidine

[1312] 4-Amino-1-(6-butoxyhexyl)piperidine is prepared from4-carboxamide-1-(6-butoxyhexyl)piperidine essentially as described abovein Example 38, Scheme B, step b.

[1313] Method 2

[1314] Scheme C, Step a: 1-(6-Butoxyhexyl)-4-piperidone

[1315] 1-(6-Butoxyhexyl)-4-piperidone is prepared from 4-piperidone and1-chloro-6-butoxyhexane essentially as described above in Example 38,Scheme C, step a.

[1316] Scheme C, Step b: 1-(6-Butoxyhexyl)-4-piperidone Oxime

[1317] 1-(6-Butoxyhexyl)-4-piperidone oxime is prepared from1-(6-butoxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1318] Scheme C, Step c: 4-Amino-1-(6-butoxyhexyl)piperidine

[1319] 4-Amino-1-(6-butoxyhexyl)piperidine is prepared from1-(6-butoxyhexyl)-4-piperidone oxime essentially as described above inExample 38, Scheme C, step c.

[1320] Scheme A, Step b:2-Chloro-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1321]2-Chloro-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-butoxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1322] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1323]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-butoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 942-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1324] Preparation of 4-Amino-1-(6-benzyloxyhexyl)piperidine

[1325] Method 1

[1326] Scheme B, Step a: 4-Carboxamide-1-(6-Benzyloxyhexyl)piperidine

[1327] 4-Carboxamide-1-(6-Benzyloxyhexyl)piperidine may be prepared fromisonipecotamide and 1-chloro-6-benzyloxyhexane essentially as describedabove in Example 38, Scheme B, step a.

[1328] Scheme B, Step b: 4-Amino-1-(6-benzyloxyhexyl)piperidine

[1329] 4-Amino-1-(6-benzyloxyhexyl)piperidine is prepared from4-carboxamide-1-(6-benzyloxyhexyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[1330] Method 2

[1331] Scheme C, Step a: 1-(6-Benzyloxyhexyl)-4-piperidone

[1332] 1-(6-Benzyloxyhexyl)-4-piperidone is prepared from 4-piperidoneand 1-chloro-6-benzyloxyhexane essentially as described above in Example38, Scheme C, step a.

[1333] Scheme C, Step b: 1-(6-Benzyloxyhexyl)-4-piperidone Oxime

[1334] 1-(6-Benzyloxyhexyl)-4-piperidone oxime is prepared from1-(6-benzyloxyhexyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1335] Scheme C, Step c: 4-Amino-1-(6-benzyloxyhexyl)piperidine

[1336] 4-Amino-1-(6-benzyloxyhexyl)piperidine is prepared from1-(6-benzyloxyhexyl)-4-piperidone oxime essentially as described abovein Example 38, Scheme C, step c.

[1337] Scheme A, Step b:2-Chloro-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1338]2-Chloro-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-benzyloxyhexyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[1339] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1340]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-benzyloxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 952-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1341] Preparation of 4-Amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine

[1342] Method 1

[1343] Scheme B, Step a:4-Carboxamide-1-(6-(2-phenylethyleneoxy)hexyl)piperidine

[1344] 4-Carboxamide-1-(6-(2-phenylethyleneoxy)hexyl)piperidine may beprepared from isonipecotamide and 1-chloro-6-(2-phenylethyleneoxy)hexaneessentially as described above in Example 38, Scheme B, step a.

[1345] Scheme B, Step b:4-Amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine

[1346] 4-Amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine is preparedfrom 4-carboxamide-1-(6-(2-phenylethyleneoxy)hexyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1347] Method 2

[1348] Scheme C, Step a: 1-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidone

[1349] 1-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidone is prepared from4-piperidone and 1-chloro-6-(2-phenylethyleneoxy)hexane essentially asdescribed above in Example 38, Scheme C, step a.

[1350] Scheme C, Step b: 1-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidoneOxime

[1351] 1-(6-(2-Phenylethyleneoxy)hexyl)-4-piperidone oxime is preparedfrom 1-(6-(2-phenylethyleneoxy)hexyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1352] Scheme C, Step c:4-Amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine

[1353] 4-Amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine is preparedfrom 1-(6-(2-phenylethyleneoxy)hexyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1354] Scheme A, Step b:2-Chloro-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1355]2-Chloro-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-(2-phenylethyleneoxy)hexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1356] Scheme A, step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1357]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-(2-phenylethyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 962-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1358] Preparation of4-Amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine

[1359] Method 1

[1360] Scheme B, Step a:4-Carboxamide-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine

[1361] 4-Carboxamide-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine may beprepared from isonipecotamide and1-chloro-6-(3-phenylpropyleneoxy)hexane essentially as described abovein Example 38, Scheme B, step a.

[1362] Scheme B, Step b:4-Amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine

[1363] 4-Amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine is preparedfrom 4-carboxamide-1-(6-(3-phenylpropyleneoxy)hexyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1364] Method 2

[1365] Scheme C, Step a: 1-(6-(3-Phenylpropyleneoxy)hexyl-4-piperidone

[1366] 1-(6-(3-Phenylpropyleneoxy)hexyl-4-piperidone is prepared from4-piperidone and 1-chloro-6-(3-phenylpropyleneoxy)hexane essentially asdescribed above in Example 38, Scheme C, step a.

[1367] Scheme C, Step b: 1-(6-(3-Phenylpropyleneoxy)hexyl-4-piperidoneOxime

[1368] 1-(6-(3-Phenylpropyleneoxy)hexyl-4-piperidone oxime is preparedfrom 1-(6-(3-phenylpropyleneoxy)hexyl-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1369] Scheme C, Step c:4-Amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine

[1370] 4-Amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine is preparedfrom 1-(6-(3-phenylpropyleneoxy)hexyl-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1371] Scheme A, Step b:2-Chloro-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1372]2-Chloro-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-(3-phenylpropyleneoxy)hexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1373] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1374]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-(3-phenylpropyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 972-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1375] Preparation of 4-Amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine

[1376] Method 1

[1377] Scheme B, Step a:4-Carboxamide-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine

[1378] 4-Carboxamide-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine may beprepared from isonipecotamide and 1-chloro-6-(4-phenylbutyleneoxy)hexaneessentially as described above in Example 38, Scheme B, step a.

[1379] Scheme B, Step b:4-Amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine

[1380] 4-Amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine is preparedfrom 4-carboxamide-1-(6-(4-phenylbutyleneoxy)hexyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1381] Method 2

[1382] Scheme C, Step a: 1-(6-(4-Phenylbutyleneoxy)hexyl)-4-piperidone

[1383] 1-(6-(4-Phenylbutyleneoxy)hexyl)-4-piperidone is prepared from4-piperidone and 1-chloro-6-(4-phenylbutyleneoxy)hexane essentially asdescribed above in Example 38, Scheme C, step a.

[1384] Scheme C, Step b: 1-(6-(4-Phenylbutyleneoxy)hexyl)-4-piperidoneOxime

[1385] 1-(6-(4-Phenylbutyleneoxy)hexyl)-4-piperidone oxime is preparedfrom 1-(6-(4-phenylbutyleneoxy)hexyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1386] Scheme C, Step c:4-Amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine

[1387] 4-Amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine is preparedfrom 1-(6-(4-phenylbutyleneoxy)hexyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1388] Scheme A, Step b:2-Chloro-6-[4-(1-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1389]2-Chloro-6-[4-(1-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(6-(4-phenylbutyleneoxy)hexyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1390] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurine

[1391]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(6-(4-phenylbutyleneoxy)hexyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 982-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurine

[1392] Preparation of 4-Amino-1-(allyl)piperidine

[1393] Method 1

[1394] Scheme B, Step a: 4-Carboxamide-1-(allyl)piperidine

[1395] 4-Carboxamide-1-(allyl)piperidine may be prepared fromisonipecotamide and allyl chloride essentially as described above inExample 38, Scheme B, step a.

[1396] Scheme B, Step b: 4-Amino-1-(allyl)piperidine

[1397] 4-Amino-1-(allyl)piperidine is prepared from4-carboxamide-1-(allyl)piperidine essentially as described above inExample 38, Scheme B, step b.

[1398] Method 2

[1399] Scheme C, Step a: 1-(allyl)-4-piperidone

[1400] 1-(allyl)-4-piperidone is prepared from 4-piperidone and allylchloride essentially as described above in Example 38, Scheme C, step a.

[1401] Scheme C, Step b: 1-(allyl)-4-piperidone Oxime

[1402] 1-(allyl)-4-piperidone oxime is prepared from1-(allyl)-4-piperidone and hydroxylamine hydrochloride essentially asdescribed above in Example 38, Scheme C, step b.

[1403] Scheme C, Step c: 4-Amino-1-(allyl)piperidine

[1404] 4-Amino-1-(allyl)piperidine is prepared from1-(allyl)-4-piperidone oxime essentially as described above in Example38, Scheme C, step c.

[1405] Scheme A, Step b:2-Chloro-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurine

[1406] 2-Chloro-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(allyl)piperidine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[1407] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurine

[1408]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(allyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 992-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine

[1409] Preparation of4-Amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine

[1410] Method 1

[1411] Scheme B, Step a:4-Carboxamide-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine

[1412] 4-Carboxamide-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine may beprepared from isonipecotamide and 2-(2-chloroethoxy)ethanol essentiallyas described above in Example 38, Scheme B, step a.

[1413] Scheme B, Step b:4-Amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine

[1414] 4-Amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine is preparedfrom 4-carboxamide-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1415] Method 2

[1416] Scheme C, Step a: 1-(2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidone

[1417] 1-(2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidone is prepared from4-piperidone and 2-(2-chloroethoxy)ethanol essentially as describedabove in Example 38, Scheme C, step a.

[1418] Scheme C, Step b: 1-(2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidoneOxime

[1419] 1-(2-(2-Hydroxyethyleneoxy)ethyl)-4-piperidone oxime is preparedfrom 1-(2-(2-hydroxyethyleneoxy)ethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1420] Scheme C, Step c:4-Amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine

[1421] 4-Amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine is preparedfrom 1-(2-(2-hydroxyethyleneoxy)ethyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1422] Scheme A, Step b:2-Chloro-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine

[1423]2-Chloro-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-(2-hydroxyethyleneoxy)ethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1424] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurine

[1425]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-(2-hydroxyethyleneoxy)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1002-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1426] Preparation of 4-Amino-1-(2-N,N-dimethylaminoethyl)piperidine

[1427] Method 1

[1428] Scheme B, Step a:4-Carboxamide-1-(2-N,N-dimethylaminoethyl)piperidine

[1429] 4-Carboxamide-1-(2-N,N-dimethylaminoethyl)piperidine may beprepared from isonipecotamide and 2-N,N-dimethylaminoethyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1430] Scheme B, Step b: 4-Amino-1-(2-N,N-dimethylaminoethyl)piperidine

[1431] 4-Amino-1-(2-N,N-dimethylaminoethyl)piperidine is prepared from4-carboxamide-1-(2-N,N-dimethylaminoethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1432] Method 2

[1433] Scheme C, Step a: 1-(2-N,N-dimethylaminoethyl)-4-piperidone

[1434] 1-(2-N,N-dimethylaminoethyl)-4-piperidone is prepared from4-piperidone and 2-N,N-dimethylaminoethyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1435] Scheme C, Step b: 1-(2-N,N-dimethylaminoethyl)-4-piperidone Oxime

[1436] 1-(2-N,N-dimethylaminoethyl)-4-piperidone oxime is prepared from1-(2-N,N-dimethylaminoethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1437] Scheme C, Step c: 4-Amino-1-(2-N,N-dimethylaminoethyl)piperidine

[1438] 4-Amino-1-(2-N,N-dimethylaminoethyl)piperidine is prepared from1-(2-N,N-dimethylaminoethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1439] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1440]2-Chloro-6-[4-(1-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-dimethylaminoethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1441] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dimethylaminoethyl)piperidinylamino]-9-cyclopentylpurine

[1442]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-dimethylaminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1012-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1443] Preparation of 4-Amino-1-(3-N,N-dimethylaminopropyl)piperidine

[1444] Method 1

[1445] Scheme B, Step a:4-Carboxamide-1-(3-N,N-dimethylaminopropyl)piperidine

[1446] 4-Carboxamide-1-(3-N,N-dimethylaminopropyl)piperidine may beprepared from isonipecotamide and 3-N,N-dimethylaminopropyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1447] Scheme B, Step b: 4-Amino-1-(3-N,N-dimethylaminopropyl)piperidine

[1448] 4-Amino-1-(3-N,N-dimethylaminopropyl)piperidine is prepared from4-carboxamide-1-(3-N,N-dimethylaminopropyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1449] Method 2

[1450] Scheme C, Step a: 1-(3-N,N-dimethylaminopropyl)-4-piperidone

[1451] 1-(3-N,N-dimethylaminopropyl)-4-piperidone is prepared from4-piperidone and 3-N,N-dimethylaminopropyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1452] Scheme C, Step b: 1-(3-N,N-dimethylaminopropyl)-4-piperidoneOxime

[1453] 1-(3-N,N-dimethylaminopropyl)-4-piperidone oxime is prepared from1-(3-N,N-dimethylaminopropyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1454] Scheme C, Step c: 4-Amino-1-(3-N,N-dimethylaminopropyl)piperidine

[1455] 4-Amino-1-(3-N,N-dimethylaminopropyl)piperidine is prepared from1-(3-N,N-dimethylaminopropyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1456] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-dimethylaminopropyl)piperidinylamino]-9-cyclopentylpurine

[1457]2-Chloro-6-[4-(1-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-dimethylaminopropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1458] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1459]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-dimethylaminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1022-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1460] Preparation of 4-Amino-1-(4-N,N-dimethylaminobutyl)piperidine

[1461] Method 1

[1462] Scheme B, Step a:4-Carboxamide-1-(4-N,N-dimethylaminobutyl)piperidine

[1463] 4-Carboxamide-1-(4-N,N-dimethylaminobutyl)piperidine may beprepared from isonipecotamide and 3-N,N-dimethylaminobutyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1464] Scheme B, Step b: Amino-1-(4-N,N-dimethylaminobutyl)piperidine

[1465] 4-Amino-1-(4-N,N-dimethylaminobutyl)piperidine is prepared from4-carboxamide-1-(4-N,N-dimethylaminobutyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1466] Method 2

[1467] Scheme C, Step a: 1-(4-N,N-dimethylaminobutyl)-4-piperidone

[1468] 1-(4-N,N-dimethylaminobutyl)-4-piperidone is prepared from4-piperidone and 3-N,N-dimethylaminobutyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1469] Scheme C, Step b: 1-(4-N,N-dimethylaminobutyl)-4-piperidone Oxime

[1470] 1-(4-N,N-dimethylaminobutyl)-4-piperidone oxime is prepared from1-(4-N,N-dimethylaminobutyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1471] Scheme C, Step c: 4-Amino-1-(4-N,N-dimethylaminobutyl)piperidine

[1472] 4-Amino-1-(4-N,N-dimethylaminobutyl)piperidine is prepared from1-(4-N,N-dimethylaminobutyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1473] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1474]2-Chloro-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-dimethylaminobutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1475] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1476]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-dimethylaminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1032-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1477] Preparation of 4-Amino-1-(5-N,N-dimethylaminopentyl)piperidine

[1478] Method 1

[1479] Scheme B, Step a:4-Carboxamide-1-(5-N,N-dimethylaminopentyl)piperidine

[1480] 4-Carboxamide-1-(5-N,N-dimethylaminopentyl)piperidine may beprepared from isonipecotamide and 5-N,N-dimethylaminopentyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1481] Scheme B, Step b: 4-Amino-1-(5-N,N-dimethylaminopentyl)piperidine

[1482] 4-Amino-1-(5-N,N-dimethylaminopentyl)piperidine is prepared from4-carboxamide-1-(5-N,N-dimethylaminopentyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1483] Method 2

[1484] Scheme C, Step a: 1-(5-N,N-dimethylaminopentyl)-4-piperidone

[1485] 1-(5-N,N-dimethylaminopentyl)-4-piperidone is prepared from4-piperidone and 5-N,N-dimethylaminopentyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1486] Scheme C, Step b: 1-(5-N,N-dimethylaminopentyl)-4-piperidoneOxime

[1487] 1-(5-N,N-dimethylaminopentyl)-4-piperidone oxime is prepared from1-(5-N,N-dimethylaminopentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1488] Scheme C, Step c: 4-Amino-1-(5-N,N-dimethylaminopentyl)piperidine

[1489] 4-Amino-1-(5-N,N-dimethylaminopentyl)piperidine is prepared from1-(5-N,N-dimethylaminopentyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1490] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1491]2-Chloro-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-dimethylaminopentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1492] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1493]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-dimethylaminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1042-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-diethylaminoethyl)piperidinylamino]-9-cyclopentylpurine

[1494] Preparation of 4-Amino-1-(2-N,N-diethylaminoethyl)piperidine

[1495] Method 1

[1496] Scheme B, Step a:4-Carboxamide-1-(2-N,N-diethylaminoethyl)piperidine

[1497] 4-Carboxamide-1-(2-N,N-diethylaminoethyl)piperidine may beprepared from isonipecotamide and 2-N,N-diethylaminoethyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1498] Scheme B, Step b: 4-Amino-1-(2-N,N-diethylaminoethyl)piperidine

[1499] 4-Amino-1-(2-N,N-diethylaminoethyl)piperidine is prepared from4-carboxamide-1-(2-N,N-diethylaminoethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1500] Method 2

[1501] Scheme C, Step a: 1-(2-N,N-diethylaminoethyl)-4-piperidone

[1502] 1-(2-N,N-diethylaminoethyl)-4-piperidone is prepared from4-piperidone and 2-N,N-diethylaminoethyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1503] Scheme C, Step b: 1-(2-N,N-diethylaminoethyl)-4-piperidone Oxime

[1504] 1-(2-N,N-diethylaminoethyl)-4-piperidone oxime is prepared from1-(2-N,N-diethylaminoethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1505] Scheme C, Step c: 4-Amino-1-(2-N,N-diethylaminoethyl)piperidine

[1506] 4-Amino-1-(2-N,N-diethylaminoethyl)piperidine is prepared from1-(2-N,N-diethylaminoethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1507] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1508]2-Chloro-6-[4-(1-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-diethylaminoethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1509] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1510]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-diethylaminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1052-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1511] Preparation of 4-Amino-1-(3-N,N-diethylaminopropyl)piperidine

[1512] Method 1

[1513] Scheme B, Step a:4-Carboxamide-1-(3-N,N-diethylaminopropyl)piperidine

[1514] 4-Carboxamide-1-(3-N,N-diethylaminopropyl)piperidine may beprepared from isonipecotamide and 3-N,N-diethylaminopropyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1515] Scheme B, Step b: 4-Amino-1-(3-N,N-diethylaminopropyl)piperidine

[1516] 4-Amino-1-(3-N,N-diethylaminopropyl)piperidine is prepared from4-carboxamide-1-(3-N,N-diethylaminopropyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1517] Method 2

[1518] Scheme C, Step a: 1-(3-N,N-diethylaminopropyl)-4-piperidone

[1519] 1-(3-N,N-diethylaminopropyl)-4-piperidone is prepared from4-piperidone and 3-N,N-diethylaminopropyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1520] Scheme C, Step b: 1-(3-N,N-diethylaminopropyl)-4-piperidone Oxime

[1521] 1-(3-N,N-diethylaminopropyl)-4-piperidone oxime is prepared from1-(3-N,N-diethylaminopropyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1522] Scheme C, Step c: 4-Amino-1-(3-N,N-diethylaminopropyl)piperidine

[1523] 4-Amino-1-(3-N,N-diethylaminopropyl)piperidine is prepared from1-(3-N,N-diethylaminopropyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1524] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1525]2-Chloro-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-diethylaminopropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1526] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1527]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-diethylaminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1062-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1528] Preparation of 4-Amino-1-(4-N,N-diethylaminobutyl)piperidine

[1529] Method 1

[1530] Scheme B, Step a:4-Carboxamide-1-(4-N,N-diethylaminobutyl)piperidine

[1531] 4-Carboxamide-1-(4-N,N-diethylaminobutyl)piperidine may beprepared from isonipecotamide and 4-N,N-diethylaminobutyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1532] Scheme B, Step b: 4-Amino-1-(4-N,N-diethylaminobutyl)piperidine

[1533] 4-Amino-1-(4-N,N-diethylaminobutyl)piperidine is prepared from4-carboxamide-1-(4-N,N-diethylaminobutyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1534] Method 2

[1535] Scheme C, Step a: 1-(4-N,N-diethylaminobutyl)-4-piperidone

[1536] 1-(4-N,N-diethylaminobutyl)-4-piperidone is prepared from4-piperidone and 4-N,N-diethylaminobutyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1537] Scheme C, Step b: 1-(4-N,N-diethylaminobutyl)-4-piperidone Oxime

[1538] 1-(4-N,N-diethylaminobutyl)-4-piperidone oxime is prepared from1-(4-N,N-diethylaminobutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1539] Scheme C, Step c: 4-Amino-1-(4-N,N-diethylaminobutyl)piperidine

[1540] 4-Amino-1-(4-N,N-diethylaminobutyl)piperidine is prepared from1-(4-N,N-diethylaminobutyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1541] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1542]2-Chloro-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-diethylaminobutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1543] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1544]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-diethylaminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1072-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurine

[1545] Preparation of 4-Amino-1-(5-N,N-diethylaminopentyl)piperidine

[1546] Method 1

[1547] Scheme B, Step a:4-Carboxamide-1-(5-N,N-diethylaminopentyl)piperidine

[1548] 4-Carboxamide-1-(5-N,N-diethylaminopentyl)piperidine may beprepared from isonipecotamide and 5-N,N-diethylaminopentyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1549] Scheme B, Step b: 4-Amino-1-(5-N,N-diethylaminopentyl)piperidine

[1550] 4-Amino-1-(5-N,N-diethylaminopentyl)piperidine is prepared from4-carboxamide-1-(5-N,N-diethylaminopentyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1551] Method 2

[1552] Scheme C, Step a: 1-(5-N,N-diethylaminopentyl)-4-piperidone

[1553] 1-(5-N,N-diethylaminopentyl)-4-piperidone is prepared from4-piperidone and 5-N,N-diethylaminopentyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1554] Scheme C, Step b: 1-(5-N,N-diethylaminopentyl)-4-piperidone Oxime

[1555] 1-(5-N,N-diethylaminopentyl)-4-piperidone oxime is prepared from1-(5-N,N-diethylaminopentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1556] Scheme C, Step c: 4-Amino-1-(5-N,N-diethylaminopentyl)piperidine

[1557] 4-Amino-1-(5-N,N-diethylaminopentyl)piperidine is prepared from1-(5-N,N-diethylaminopentyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1558] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurine

[1559]2-Chloro-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-diethylaminopentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1560] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurine

[1561]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-diethylaminopentyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1082-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1562] Preparation of 4-Amino-1-(2-N,N-dipropylaminoethyl)piperidine

[1563] Method 1

[1564] Scheme B, Step a:4-Carboxamide-1-(2-N,N-dipropylaminoethyl)piperidine

[1565] 4-Carboxamide-1-(2-N,N-dipropylaminoethyl)piperidine may beprepared from isonipecotamide and 2-N,N-dipropylaminoethyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1566] Scheme B, Step b: 4-Amino-1-(2-N,N-dipropylaminoethyl)piperidine

[1567] 4-Amino-1-(2-N,N-dipropylaminoethyl)piperidine is prepared from4-carboxamide-1-(2-N,N-dipropylaminoethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1568] Method 2

[1569] Scheme C, Step a: 1-(2-N,N-dipropylaminoethyl)-4-piperidone

[1570] 1-(2-N,N-dipropylaminoethyl)-4-piperidone is prepared from4-piperidone and 2-N,N-dipropylaminoethyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1571] Scheme C, Step b: 1-(2-N,N-dipropylaminoethyl)-4-piperidone Oxime

[1572] 1-(2-N,N-dipropylaminoethyl)-4-piperidone oxime is prepared from1-(2-N,N-dipropylaminoethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1573] Scheme C, Step c: 4-Amino-1-(2-N,N-dipropylaminoethyl)piperidine

[1574] 4-Amino-1-(2-N,N-dipropylaminoethyl)piperidine is prepared from1-(2-N,N-dipropylaminoethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1575] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1576]2-Chloro-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-dipropylaminoethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1577] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1578]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-dipropylaminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1092-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1579] Preparation of 4-Amino-1-(3-N,N-dipropylaminopropyl)piperidine

[1580] Method 1

[1581] Scheme B, Step a:4-Carboxamide-1-(3-N,N-dipropylaminopropyl)piperidine

[1582] 4-Carboxamide-1-(3-N,N-dipropylaminopropyl)piperidine may beprepared from isonipecotamide and 3-N,N-dipropylaminopropyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1583] Scheme B, Step b: 4-Amino-1-(3-N,N-dipropylaminopropyl)piperidine

[1584] 4-Amino-1-(3-N,N-dipropylaminopropyl)piperidine is prepared from4-carboxamide-1-(3-N,N-dipropylaminopropyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1585] Method 2

[1586] Scheme C, Step a: 1-(3-N,N-dipropylaminopropyl)-4-piperidone

[1587] 1-(3-N,N-dipropylaminopropyl)-4-piperidone is prepared from4-piperidone and 3-N,N-dipropylaminopropyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1588] Scheme C, Step b: 1-(3-N,N-dipropylaminopropyl)-4-piperidoneOxime

[1589] 1-(3-N,N-dipropylaminopropyl)-4-piperidone oxime is prepared from1-(3-N,N-dipropylaminopropyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1590] Scheme C, Step c: 4-Amino-1-(3-N,N-dipropylaminopropyl)piperidine

[1591] 4-Amino-1-(3-N,N-dipropylaminopropyl)piperidine is prepared from1-(3-N,N-dipropylaminopropyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1592] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1593]2-Chloro-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-dipropylaminopropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1594] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1595]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-dipropylaminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1102-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1596] Preparation of 4-Amino-1-(4-N,N-dipropylaminobutyl)piperidine

[1597] Method 1

[1598] Scheme B, Step a:4-Carboxamide-1-(4-N,N-dipropylaminobutyl)piperidine

[1599] 4-Carboxamide-1-(4-N,N-dipropylaminobutyl)piperidine may beprepared from isonipecotamide and 4-N,N-dipropylaminobutyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1600] Scheme B, Step b: 4-Amino-1-(4-N,N-dipropylaminobutyl)piperidine

[1601] 4-Amino-1-(4-N,N-dipropylaminobutyl)piperidine is prepared from4-carboxamide-1-(4-N,N-dipropylaminobutyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1602] Method 2

[1603] Scheme C, Step a: 1-(4-N,N-dipropylaminobutyl)-4-piperidone

[1604] 1-(4-N,N-dipropylaminobutyl)-4-piperidone is prepared from4-piperidone and 4-N,N-dipropylaminobutyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1605] Scheme C, Step b: 1-(4-N,N-dipropylaminobutyl)-4-piperidone Oxime

[1606] 1-(4-N,N-dipropylaminobutyl)-4-piperidone oxime is prepared from1-(4-N,N-dipropylaminobutyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1607] Scheme C, Step c: 4-Amino-1-(4-N,N-dipropylaminobutyl)piperidine

[1608] 4-Amino-1-(4-N,N-dipropylaminobutyl)piperidine is prepared from1-(4-N,N-dipropylaminobutyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1609] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1610]2-Chloro-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-dipropylaminobutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1611] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1612]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-dipropylaminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1112-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1613] Preparation of 4-Amino-1-(5-N,N-dipropylaminopentyl)piperidine

[1614] Method 1

[1615] Scheme B, Step a:4-Carboxamide-1-(5-N,N-dipropylaminopentyl)piperidine

[1616] 4-Carboxamide-1-(5-N,N-dipropylaminopentyl)piperidine may beprepared from isonipecotamide and 5-N,N-dipropylaminopentyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1617] Scheme B, Step b: 4-Amino-1-(5-N,N-dipropylaminopentyl)piperidine

[1618] 4-Amino-1-(5-N,N-dipropylaminopentyl)piperidine is prepared from4-carboxamide-1-(5-N,N-dipropylaminopentyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1619] Method 2

[1620] Scheme C, Step a: 1-(5-N,N-dipropylaminopentyl)-4-piperidone

[1621] 1-(5-N,N-dipropylaminopentyl)-4-piperidone is prepared from4-piperidone and 5-N,N-dipropylaminopentyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1622] Scheme C, Step b: 1-(5-N,N-dipropylaminopentyl)-4-piperidoneOxime

[1623] 1-(5-N,N-dipropylaminopentyl)-4-piperidone oxime is prepared from1-(5-N,N-dipropylaminopentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1624] Scheme C, Step c: 4-Amino-1-(5-N,N-dipropylaminopentyl)piperidine

[1625] 4-Amino-1-(5-N,N-dipropylaminopentyl)piperidine is prepared from1-(5-N,N-dipropylaminopentyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1626] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1627]2-Chloro-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-dipropylaminopentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1628] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1629]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-dipropylaminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1122-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1630] Preparation of 4-Amino-1-(2-N,N-dibutylaminoethyl)piperidine

[1631] Method 1

[1632] Scheme B, Step a:4-Carboxamide-1-(2-N,N-dibutylaminoethyl)piperidine

[1633] 4-Carboxamide-1-(2-N,N-dibutylaminoethyl)piperidine may beprepared from isonipecotamide and 2-N,N-dibutylaminoethyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1634] Scheme B, Step b: 4-Amino-1-(2-N,N-dibutylaminoethyl)piperidine

[1635] 4-Amino-1-(2-N,N-dibutylaminoethyl)piperidine is prepared from4-carboxamide-1-(2-N,N-dibutylaminoethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1636] Method 2

[1637] Scheme C, Step a: 1-(2-N,N-butylaminoethyl)-4-piperidone

[1638] 1-(2-N,N-dibutylaminoethyl)-4-piperidone is prepared from4-piperidone and 2-N,N-dibutylaminoethyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1639] Scheme C, Step b: 1-(2-N,N-dibutylaminoethyl)-4-piperidone Oxime

[1640] 1-(2-N,N-dibutylaminoethyl)-4-piperidone oxime is prepared from1-(2-N,N-dibutylaminoethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1641] Scheme C, Step c: 4-Amino-1-(2-N,N-dibutylaminoethyl)piperidine

[1642] 4-Amino-1-(2-N,N-dibutylaminoethyl)piperidine is prepared from1-(2-N,N-dibutylaminoethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1643] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1644]2-Chloro-6-[4-(1-(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-dibutylaminoethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1645] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-(2-N,N-dibutylaminoethyl)piperidinylamino]-9-cyclopentylpurine

[1646]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-dibutylaminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1132-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1647] Preparation of 4-Amino-1-(3-N,N-dibutylaminopropyl)piperidine

[1648] Method 1

[1649] Scheme B, Step a:4-Carboxamide-1-(3-N,N-dibutylaminopropyl)piperidine

[1650] 4-Carboxamide-1-(3-N,N-dibutylaminopropyl)piperidine may beprepared from isonipecotamide and 3-N,N-dibutylaminopropyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1651] Scheme B, Step b: 4-Amino-1-(3-N,N-dibutylaminopropyl)piperidine

[1652] 4-Amino-1-(3-N,N-dibutylaminopropyl)piperidine is prepared from4-carboxamide-1-(3-N,N-dibutylaminopropyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1653] Method 2

[1654] Scheme C, Step a: 1-(3-N,N-dibutylaminopropyl)-4-piperidone

[1655] 1-(3-N,N-dibutylaminopropyl)-4-piperidone is prepared from4-piperidone and 3-N,N-dibutylaminopropyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1656] Scheme C, Step b: 1-(3-N,N-dibutylaminopropyl)-4-piperidone Oxime

[1657] 1-(3-N,N-dibutylaminopropyl)-4-piperidone oxime is prepared from1-(3-N,N-dibutylaminopropyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1658] Scheme C, Step c: 4-Amino-1-(3-N,N-dibutylaminopropyl)piperidine

[1659] 4-Amino-1-(3-N,N-dibutylaminopropyl)piperidine is prepared from1-(3-N,N-dibutylaminopropyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1660] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1661]2-Chloro-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-dibutylaminopropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1662] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1663]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-dibutylaminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1142-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine

[1664] Preparation of 4-Amino-1-(4-N,N-dibutylaminobutyl)piperidine

[1665] Method 1

[1666] Scheme B, Step a:4-Carboxamide-1-(4-N,N-dibutylaminobutyl)piperidine

[1667] 4-Carboxamide-1-(4-N,N-dibutylaminobutyl)piperidine may beprepared from isonipecotamide and 4-N,N-dibutylaminobutyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1668] Scheme B, Step b: 4-Amino-1-(4-N,N-dibutylaminobutyl)piperidine

[1669] 4-Amino-1-(4-N,N-dibutylaminobutyl)piperidine is prepared from4-carboxamide-1-(4-N,N-dibutylaminobutyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1670] Method 2

[1671] Scheme C, Step a: 1-(4-N,N-dibutylaminobutyl)-4-piperidone

[1672] 1-(4-N,N-dibutylaminobutyl)-4-piperidone is prepared from4-piperidone and 4-N,N-dibutylaminobutyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1673] Scheme C, Step b: 1-(4-N,N-dibutylaminobutyl)-4-piperidone Oxime

[1674] 1-(4-N,N-dibutylaminobutyl)-4-piperidone oxime is prepared from1-(4-N,N-dibutylaminobutyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1675] Scheme C, Step c: 4-Amino-1-(4-N,N-dibutylaminobutyl)piperidine

[1676] 4-Amino-1-(4-N,N-dibutylaminobutyl)piperidine is prepared from1-(4-N,N-dibutylaminobutyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1677] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine

[1678]2-Chloro-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-dibutylaminobutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1679] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurine

[1680]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-dibutylaminobutyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1152-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1681] Preparation of 4-Amino-1-(5-N,N-dibutylaminopentyl)piperidine

[1682] Method 1

[1683] Scheme B, Step a:4-Carboxamide-1-(5-N,N-dibutylaminopentyl)piperidine

[1684] 4-Carboxamide-1-(5-N,N-dibutylaminopentyl)piperidine may beprepared from isonipecotamide and 5-N,N-dibutylaminopentyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1685] Scheme B, Step b: 4-Amino-1-(5-N,N-dibutylaminopentyl)piperidine

[1686] 4-Amino-1-(5-N,N-dibutylaminopentyl)piperidine is prepared from4-carboxamide-1-(5-N,N-dibutylaminopentyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1687] Method 2

[1688] Scheme C, Step a: 1-(5-N,N-dibutylaminopentyl)-4-piperidone

[1689] 1-(5-N,N-dibutylaminopentyl)-4-piperidone is prepared from4-piperidone and 5-N,N-dibutylaminopentyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1690] Scheme C, Step b: 1-(5-N,N-dibutylaminopentyl)-piperidone Oxime

[1691] 1-(5-N,N-dibutylaminopentyl)-4-piperidone oxime is prepared from1-(5-N,N-dibutylaminopentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1692] Scheme C, Step c: 4-Amino-1-(5-N,N-dibutylaminopentyl)piperidine

[1693] 4-Amino-1-(5-N,N-dibutylaminopentyl)piperidine is prepared from1-(5-N,N-dibutylaminopentyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1694] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1695]2-Chloro-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-dibutylaminopentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1696] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1697]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-dibutylaminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1162-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1698] Preparation of 4-Amino-1-(2-N,N-dibenzylaminoethyl)piperidine

[1699] Method 1

[1700] Scheme B, Step a:4-Carboxamide-1-(2-N,N-dibenzylaminoethyl)piperidine

[1701] 4-Carboxamide-1-(2-N,N-dibenzylaminoethyl)piperidine may beprepared from isonipecotamide and 2-N,N-dibenzylaminoethyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1702] Scheme B, Step b: 4-Amino-1-(2-N,N-dibenzylaminoethyl)piperidine

[1703] 4-Amino-1-(2-N,N-dibenzylaminoethyl)piperidine is prepared from4-carboxamide-1-(2-N,N-dibenzylaminoethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1704] Method 2

[1705] Scheme C, Step a: 1-(2-N,N-dibenzylaminoethyl)-4-piperidone

[1706] 1-(2-N,N-dibenzylaminoethyl)-4-piperidone is prepared from4-piperidone and 2-N,N-dibenzylaminoethyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1707] Scheme C, Step b: 1-(2-N,N-dibenzylaminoethyl)-4-piperidone Oxime

[1708] 1-(2-N,N-dibenzylaminoethyl)-4-piperidone oxime is prepared from1-(2-N,N-dibenzylaminoethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1709] Scheme C, Step c: 4-Amino-1-(2-N,N-dibenzylaminoethyl)piperidine

[1710] 4-Amino-1-(2-N,N-dibenzylaminoethyl)piperidine is prepared from1-(2-N,N-dibenzylaminoethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1711] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-dibenzlaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1712]2-Chloro-6-[4-(1-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-dibenzylaminoethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1713] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurine

[1714]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-dibenzylaminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1172-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1715] Preparation of 4-Amino-1-(3-N,N-dibenzylaminopropyl)piperidine

[1716] Method 1

[1717] Scheme B, Step a:4-Carboxamide-1-(3-N,N-dibenzylaminopropyl)piperidine

[1718] 4-Carboxamide-1-(3-N,N-dibenzylaminopropyl)piperidine may beprepared from isonipecotamide and 3-N,N-dibenzylaminopropyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1719] Scheme B, Step b: 4-Amino-1-(3-N,N-dibenzylaminopropyl)piperidine

[1720] 4-Amino-1-(3-N,N-dibenzylaminopropyl)piperidine is prepared from4-carboxamide-1-(3-N,N-dibenzylaminopropyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1721] Method 2

[1722] Scheme C, Step a: 1-(3-N,N-dibenzylaminopropyl)-4-piperidone

[1723] 1-(3-N,N-dibenzylaminopropyl)-4-piperidone is prepared from4-piperidone and 3-N,N-dibenzylaminopropyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1724] Scheme C, Step b: 1-(3-N,N-dibenzylaminopropyl)-4-piperidoneOxime

[1725] 1-(3-N,N-dibenzylaminopropyl)-4-piperidone oxime is prepared from1-(3-N,N-dibenzylaminopropyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1726] Scheme C, Step c: 4-Amino-1-(3-N,N-dibenzylaminopropyl)piperidine

[1727] 4-Amino-1-(3-N,N-dibenzylaminopropyl)piperidine is prepared from1-(3-N,N-dibenzylaminopropyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1728] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1729]2-Chloro-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-dibenzylaminopropyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1730] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurine

[1731]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-dibenzylaminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1182-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1732] Preparation of 4-Amino-1-(4-N,N-dibenzylaminobutyl)piperidine

[1733] Method 1

[1734] Scheme B, Step a:4-Carboxamide-1-(4-N,N-dibenzylaminobutyl)piperidine

[1735] 4-Carboxamide-1-(4-N,N-dibenzylaminobutyl)piperidine may beprepared from isonipecotamide and 4-N,N-dibenzylaminobutyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1736] Scheme B, Step b: 4-Amino-1-(4-N,N-dibenzylaminobutyl)piperidine

[1737] 4-Amino-1-(4-N,N-dibenzylaminobutyl)piperidine is prepared from4-carboxamide-1-(4-N,N-dibenzylaminobutyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1738] Method 2

[1739] Scheme C, Step a: 1-(4-N,N-dibenzylaminobutyl)-4-piperidone

[1740] 1-(4-N,N-dibenzylaminobutyl)-4-piperidone is prepared from4-piperidone and 4-N,N-dibenzylaminobutyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1741] Scheme C, Step b: 1-[4-N,N-dibenzylaminobutyl)-4-piperidone Oxime

[1742] 1-(4-N,N-dibenzylaminobutyl)-4-piperidone oxime is prepared from1-(4-N,N-dibenzylaminobutyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1743] Scheme C, Step c: 4-Amino-1-(4-N,N-dibenzylaminobutyl)piperidine

[1744] 4-Amino-1-(4-N,N-dibenzylaminobutyl)piperidine is prepared from1-(4-N,N-dibenzylaminobutyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[1745] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1746]2-Chloro-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-dibenzylaminobutyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1747] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurine

[1748]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-dibenzylaminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1192-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1749] Preparation of 4-Amino-1-(5-N,N-dibenzylaminopentyl)piperidine

[1750] Method 1

[1751] Scheme B, Step a:4-Carboxamide-1-(5-N,N-dibenzylaminopentyl)piperidine

[1752] 4-Carboxamide-1-(5-N,N-dibenzylaminopentyl)piperidine may beprepared from isonipecotamide and 5-N,N-dibenzylaminopentyl chlorideessentially as described above in Example 38, Scheme B, step a.

[1753] Scheme B, Step b: 4-Amino-1-(5-N,N-dibenzylaminopentyl)piperidine

[1754] 4-Amino-1-(5-N,N-dibenzylaminopentyl)piperidine is prepared from4-carboxamide-1-(5-N,N-dibenzylaminopentyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1755] Method 2

[1756] Scheme C, Step a: 1-(5-N,N-dibenzylaminopentyl)-4-piperidone

[1757] 1-(5-N,N-dibenzylaminopentyl)-4-piperidone is prepared from4-piperidone and 5-N,N-dibenzylaminopentyl chloride essentially asdescribed above in Example 38, Scheme C, step a.

[1758] Scheme C, Step b: 1-(5-N,N-dibenzylaminopentyl)-4-piperidoneOxime

[1759] 1-(5-N,N-dibenzylaminopentyl)-4-piperidone oxime is prepared from1-(5-N,N-dibenzylaminopentyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1760] Scheme C, Step c: 4-Amino-1-(5-N,N-dibenzylaminopentyl)piperidine

[1761] 4-Amino-1-(5-N,N-dibenzylaminopentyl)piperidine is prepared from1-(5-N,N-dibenzylaminopentyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1762] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1763]2-Chloro-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-dibenzylaminopentyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1764] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurine

[1765]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-dibenzylaminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1202-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1766] Preparation of4-Amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine

[1767] Method 1

[1768] Scheme B, Step a:4-Carboxamide-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine

[1769] 4-Carboxamide-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidinemay be prepared from isonipecotamide and2-N,N-di-(2-phenylethyleneamino)ethyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1770] Scheme B, Step b:4-Amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine

[1771] 4-Amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine isprepared from4-carboxamide-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1772] Method 2

[1773] Scheme C, Step a:1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone

[1774] 1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone isprepared from 4-piperidone and 2-N,N-di-(2-phenylethyleneamino)ethylchloride essentially as described above in Example 38, Scheme C, step a.

[1775] Scheme C, Step b:1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone Oxime

[1776] 1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone oxime isprepared from 1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[1777] Scheme C, Step c:4-Amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine

[1778] 4-Amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine isprepared from 1-(2-N,N-di-(2-phenylethylene)aminoethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1779] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1780]2-Chloro-6-[4-(1-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-di-(2-phenylethylene)aminoethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1781] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1782]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-2-phenylethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-di-(2-phenyethylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1212-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1783] Preparation of4-Amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine

[1784] Method 1

[1785] Scheme B, Step a:4-Carboxamide-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine

[1786]4-Carboxamide-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine maybe prepared from isonipecotamide and3-N,N-di-(2-phenylethyleneamino)propyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1787] Scheme B, Step b:4-Amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine

[1788] 4-Amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine isprepared from4-carboxamide-1-(3-N,N-di-2-phenylethylene)aminopropyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1789] Method 2

[1790] Scheme C, Step a:1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone

[1791] 1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone isprepared from 4-piperidone and 3-N,N-di-(2-phenylethyleneamino)propylchloride essentially as described above in Example 38, Scheme C, step a.

[1792] Scheme C, Step b:1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone Oxime

[1793] 1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidone oxime isprepared from 1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1794] Scheme C, Step c:4-Amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine

[1795] 4-Amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine isprepared from 1-(3-N,N-di-(2-phenylethylene)aminopropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1796] Scheme A, Step b:2-Chloro-6-[4-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1797]2-Chloro-6-[4-(1-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-di-(2-phenylethylene)aminopropyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1798] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1799]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-di-(2-phenylethylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1222-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1800] Preparation of4-Amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine

[1801] Method 1

[1802] Scheme B, Step a:4-Carboxamide-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine

[1803] 4-Carboxamide-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidinemay be prepared from isonipecotamide and4-N,N-di-(2-phenylethyleneamino)butyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1804] Scheme B, Step b:4-Amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine

[1805] 4-Amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine isprepared from4-carboxamide-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1806] Method 2

[1807] Scheme C, Step a:1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone

[1808] 1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone isprepared from 4-piperidone and 4-N,N-di-(2-phenylethyleneamino)butylchloride essentially as described above in Example 38, Scheme C, step a.

[1809] Scheme C, Step b:1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone Oxime

[1810] 1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone oxime isprepared from 1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[1811] Scheme C, Step c:4-Amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine

[1812] 4-Amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine isprepared from 1-(4-N,N-di-(2-phenylethylene)aminobutyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1813] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1814]2-Chloro-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-di-(2-phenylethylene)aminobutyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1815] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1816]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-di-(2-phenylethylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1232-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1817] Preparation of4-Amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine

[1818] Method 1

[1819] Scheme B, Step a:4-Carboxamide-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine

[1820]4-Carboxamide-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine maybe prepared from isonipecotamide and5-N,N-di-(2-phenylethyleneamino)pentyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1821] Scheme B, Step b:4-Amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine

[1822] 4-Amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine isprepared from4-carboxamide-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1823] Method 2

[1824] Scheme C, Step a:1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone

[1825] 1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone isprepared from 4-piperidone and 5-N,N-di-(2-phenylethyleneamino)pentylchloride essentially as described above in Example 38, Scheme C, step a.

[1826] Scheme C, Step b:1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone Oxime

[1827] 1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidone oxime isprepared from 1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1828] Scheme C, Step c:4-Amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine

[1829] 4-Amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine isprepared from 1-(5-N,N-di-(2-phenylethylene)aminopentyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1830] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1831]2-Chloro-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-di-(2-phenylethylene)aminopentyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1832] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurine

[1833]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-di-(2-phenylethylene)aminopentyl))-piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1242-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1834] Preparation of4-Amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine

[1835] Method 1

[1836] Scheme B, Step a:4-Carboxamide-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine

[1837]4-Carboxamide-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine maybe prepared from isonipecotamide and2-N,N-di-(3-phenylpropyleneamino)ethyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1838] Scheme B, Step b:4-Amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine

[1839] 4-Amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine isprepared from4-carboxamide-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1840] Method 2

[1841] Scheme C, Step a:1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone

[1842] 1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone isprepared from 4-piperidone and 2-N,N-di-(3-phenylpropyleneamino)ethylchloride essentially as described above in Example 38, Scheme C, step a.

[1843] Scheme C, Step b:1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone Oxime

[1844] 1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidone oxime isprepared from 1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1845] Scheme C, Step c:4-Amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine

[1846] 4-Amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine isprepared from 1-(2-N,N-di-(3-phenylpropylene)aminoethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step C.

[1847] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1848]2-Chloro-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1849] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl)piperidinylamino]-9-cyclopentylpurine

[1850]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-di-(3-phenylpropylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1252-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1851] Preparation of4-Amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine

[1852] Method 1

[1853] Scheme B, Step a:4-Carboxamide-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine

[1854]4-Carboxamide-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine maybe prepared from isonipecotamide and3-N,N-di-(3-phenylpropyleneamino)propyl chloride essentially asdescribed above in Example 38, Scheme B, step a.

[1855] Scheme B, Step b:4-Amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine

[1856] 4-Amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine isprepared from4-carboxamide-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1857] Method 2

[1858] Scheme C, Step a:1-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone

[1859] 1-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone isprepared from 4-piperidone and 3-N,N-di-(3-phenylpropyleneamino)propylchloride essentially as described above in Example 38, Scheme C, step a.

[1860] Scheme C, Step b:1-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone Oxime

[1861] 1-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidone oxime isprepared from 1-(3-N,N-di-(3-phenylpropylene)aminopropyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1862] Scheme C, Step c:4-Amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine

[1863] 4-Amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine isprepared from 1-(3-N,N-(3-phenylpropylene)aminopropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1864] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1865]2-Chloro-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-di-(3-phenylpropylene)aminopropyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1866] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1867]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-di-(3-phenylpropylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1262-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1868] Preparation of4-Amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine

[1869] Method 1

[1870] Scheme B, Step a:4-Carboxamide-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine

[1871]4-Carboxamide-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine maybe prepared from isonipecotamide and4-N,N-di-(3-phenylpropyleneamino)butyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1872] Scheme B, Step b:4-Amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine

[1873] 4-Amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine isprepared from4-carboxamide-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1874] Method 2

[1875] Scheme C, Step a:1-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone

[1876] 1-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone isprepared from 4-piperidone and 4-N,N-di-(3-phenylpropyleneamino)butylchloride essentially as described above in Example 38, Scheme C, step a.

[1877] Scheme C, Step b:1-(4N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone Oxime

[1878] 1-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidone oxime isprepared from 1-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1879] Scheme C, Step c:4-Amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine

[1880] 4-Amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine isprepared from 1-(4-N,N-di-(3-phenylpropylene)aminobutyl)-4-piperidoneOxime essentially as described above in Example 38, Scheme C, step c.

[1881] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1882]2-Chloro-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-di-(3-phenylpropylene)aminobutyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1883] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1884]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-di-(3-phenylpropylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1272-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1885] Preparation of4-Amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine

[1886] Method 1

[1887] Scheme B, Step a:4-Carboxamide-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine

[1888]4-Carboxamide-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine maybe prepared from isonipecotamide and5-N,N-di-(3-phenylpropyleneamino)pentyl chloride essentially asdescribed above in Example 38, Scheme B, step a.

[1889] Scheme B, Step b:4-Amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine

[1890] 4-Amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine isprepared from4-carboxamide-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1891] Method 2

[1892] Scheme C, Step a:1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidone

[1893] 1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidone isprepared from 4-piperidone and 5-N,N-di-(3-phenylpropyleneamino)pentylchloride essentially as described above in Example 38, Scheme C, step a.

[1894] Scheme C, Step b:1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidone Oxime

[1895] 1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidone oxime isprepared from 1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1896] Scheme C, Step c:4-Amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine

[1897] 4-Amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine isprepared from 1-(5-N,N-di-(3-phenylpropylene)aminopentyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1898] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1899]2-Chloro-6-[4-(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-di-(3-phenylpropylene)aminopentyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1900] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1901]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[(1-(5-N,N-di-(3-phenylpropylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1282-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1902] Preparation of4-Amino-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine

[1903] Method 1

[1904] Scheme B, Step a:4-Carboxamide-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine

[1905] 4-Carboxamide-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidinemay be prepared from isonipecotamide and2-N,N-di-(4-phenylbutyleneamino)ethyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1906] Scheme B, Step b:4-Amino-1-(2-N,N-di-(phenylbutylene)aminoethyl)piperidine

[1907] 4-Amino-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine isprepared from4-carboxamide-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1908] Method 2

[1909] Scheme C, Step a:1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone

[1910] 1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone isprepared from 4-piperidone and 2-N,N-di-(4-phenylbutyleneamino)ethylchloride essentially as described above in Example 38, Scheme C, step a.

[1911] Scheme C, Step b:1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone Oxime

[1912] 1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone oxime isprepared from 1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[1913] Scheme C, Step c:4-Amino-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine

[1914] 4-Amino-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine isprepared from 1-(2-N,N-di-(4-phenylbutylene)aminoethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1915] Scheme A, Step b:2-Chloro-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1916]2-Chloro-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-N,N-di-(4-phenylbutylene)aminoethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1917] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurine

[1918]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-N,N-di-(4-phenylbutylene)aminoethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1292-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-[4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1919] Preparation of4-Amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine

[1920] Method 1

[1921] Scheme B, Step a:4-Carboxamide-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine

[1922]4-Carboxamide-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine maybe prepared from isonipecotamide and3-N,N-di-(4-phenylbutyleneamino)propyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1923] Scheme B, Step b:4-Amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine

[1924] 4-Amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine isprepared from4-carboxamide-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1925] Method 2

[1926] Scheme C, Step a:1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone

[1927] 1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone isprepared from 4-piperidone and 3-N,N-di-(4-phenylbutyleneamino)propylchloride essentially as described above in Example 38, Scheme C, step a.

[1928] Scheme C, Step b:1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone Oxime

[1929] 1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidone oxime isprepared from 1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1930] Scheme C, Step c:4-Amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine

[1931] 4-Amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine isprepared from 1-(3-N,N-di-(4-phenylbutylene)aminopropyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1932] Scheme A, Step b:2-Chloro-6-[4-(1-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1933]2-Chloro-6-[4-(1-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-N,N-di-(4-phenylbutylene)aminopropyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1934] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurine

[1935]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-N,N-di-(4-phenylbutylene)aminopropyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1302-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1936] Preparation of4-Amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine

[1937] Method 1

[1938] Scheme B, Step a:4-Carboxamide-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine

[1939] 4-Carboxamide-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidinemay be prepared from isonipecotamide and4-N,N-di-(4-phenylbutyleneamino)butyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1940] Scheme B, Step b:4-Amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine

[1941] 4-Amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine isprepared from4-carboxamide-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1942] Method 2

[1943] Scheme C, Step a:1-(4-Di-(4-phenylbutylene)aminobutyl)-4-piperidone

[1944] 1-(4-(Di-(4-phenylbutylene)aminobutyl)-4-piperidone is preparedfrom 4-piperidone and 4-N,N-di-(4-phenylbutyleneamino)butyl chlorideessentially as described above in Example 38, Scheme C, step a.

[1945] Scheme C, Step b:1-(4-(Di-(4-phenylbutylene)aminobutyl)-4-piperidone Oxime

[1946] 1-(4-(Di-(4-phenylbutylene)aminobutyl)-4-piperidone oxime isprepared from 1-(4-(di-(4-phenylbutylene)aminobutyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[1947] Scheme C, Step c:4-Amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine

[1948] 4-Amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine isprepared from 1-(4-(di-(4-phenylbutylene)aminobutyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

[1949] Scheme A, Step b:2-Chloro-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidinylamino]-9-cyclopentylpurine

[1950]2-Chloro-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-N,N-di-(4-phenylbutylene)aminobutyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1951] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurine

[1952]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-N,N-di-(4-phenylbutylene)aminobutyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1312-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1953] Preparation of4-Amino-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine

[1954] Method 1

[1955] Scheme B, Step a:4-Carboxamide-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine

[1956]4-Carboxamide-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine maybe prepared from isonipecotamide and5-N,N-di-(4-phenylbutyleneamino)pentyl chloride essentially as describedabove in Example 38, Scheme B, step a.

[1957] Scheme B, Step b: 4-Amino-1-(5-N,N-di-(4-phenylbutyleneaminopentyl)piperidine

[1958] 4-Amino-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine isprepared from4-carboxamide-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[1959] Method 2

[1960] Scheme C, Step a:1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidone

[1961] 1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidone isprepared from 4-piperidone and 5-N,N-di-(4-phenylbutyleneamino)pentylchloride essentially as described above in Example 38, Scheme C, step a.

[1962] Scheme C, Step b:1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidone Oxime

[1963] 1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidone oxime isprepared from 1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[1964] Scheme C, Step c:4-Amino-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine

[1965] 4-Amino-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine isprepared from 1-(5-N,N-di-(4-phenylbutylene)aminopentyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[1966] Scheme A, Step b:2-Chloro-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1967]2-Chloro-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(5-N,N-di-(4-phenylbutylene)aminopentyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[1968] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurine

[1969]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(5-N,N-di-(4-phenylbutylene)aminopentyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1322-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine

[1970] Preparation of 4-Amino-1-(3-tetrahydrofuranylmethyl)piperidine

[1971] Method 1

[1972] Scheme B, Step a:4-Carboxamide-1-(3-tetrahydrofuranylmethyl)piperidine

[1973] 4-Carboxamide-1-(3-tetrahydrofuranylmethyl)piperidine may beprepared from isonipecotamide and tetrahydrofurfuryl chlorideessentially as described above in Example 38, Scheme B, step a.

[1974] Scheme B, Step b: 4-Amino-1-(3-tetrahydrofuranylmethyl)piperidine

[1975] 4-Amino-1-(3-tetrahydrofuranylmethyl)piperidine is prepared from4-carboxamide-1-(3-tetrahydrofuranylmethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1976] Method 2

[1977] Scheme C, Step a: 1-(3-Tetrahydrofuranylmethyl)-4-piperidone

[1978] 1-(3-Tetrahydrofuranylmethyl)-4-piperidone is prepared from4-piperidone and tetrahydrofurfuryl chloride essentially as describedabove in Example 38, Scheme C, step a.

[1979] Scheme C, Step b: 1-(3-Tetrahydrofuranylmethyl)-4-piperidoneOxime

[1980] 1-(3-Tetrahydrofuranylmethyl)-4-piperidone oxime is prepared from1-(3-tetrahydrofuranylmethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[1981] Scheme C, Step c: 4-Amino-1-(3-tetrahydrofuranylmethyl)piperidine

[1982] 4-Amino-1-(3-tetrahydrofuranylmethyl)piperidine is prepared from1-(3-tetrahydrofuranylmethyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[1983] Scheme A, Step b:2-Chloro-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine

[1984]2-Chloro-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-tetrahydrofuranylmethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[1985] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurine

[1986]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-tetrahydrofuranyl)methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1332-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[1987] Preparation of 4-Amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine

[1988] Method 1

[1989] Scheme B, Step a:4-Carboxamide-1-(2-(1-pyrrolidinyl)ethyl)piperidine

[1990] 4-Carboxamide-1-(2-(1-pyrrolidinyl)ethyl)piperidine may beprepared from isonipecotamide and 1-(2-chloroethyl)pyrrolidineessentially as described above in Example 38, Scheme B, step a.

[1991] Scheme B, Step b: 4-Amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine

[1992] 4-Amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine is prepared from4-carboxamide-1-(2-(1-pyrrolidinyl)ethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[1993] Method 2

[1994] Scheme C, Step a: 1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone

[1995] 1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone is prepared from4-piperidone and 1-(2-chloroethyl)pyrrolidine essentially as describedabove in Example 38, Scheme C, step a.

[1996] Scheme C, Step b: 1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone Oxime

[1997] 1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone oxime is prepared from1-(2-(1-pyrrolidinyl)ethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[1998] Scheme C, Step c: 4-Amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine

[1999] 4-Amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine is prepared from1-(2-(1-pyrrolidinyl)ethyl-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2000] Scheme A, Step b:2-Chloro-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2001]2-Chloro-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-(1-pyrrolidinyl)ethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2002] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2003]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-(1-pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1342-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2004] Preparation of 4-Amino-1-(2-(1-piperidinyl)ethyl)piperidine

[2005] Method 1

[2006] Scheme B, Step a:4-Carboxamide-1-(2-(1-piperidinyl)ethyl)piperidine

[2007] 4-Carboxamide-1-(2-(1-piperidinyl)ethyl)piperidine may beprepared from isonipecotamide and 1-(2-chloroethyl)piperidineessentially as described above in Example 38, Scheme B, step a.

[2008] Scheme B, Step b: 4-Amino-1-(2-(1-piperidinyl)ethyl)piperidine

[2009] 4-Amino-1-(2-(1-piperidinyl)ethyl)piperidine is prepared from4-carboxamide-1-(2-(1-piperidinyl)ethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2010] Method 2

[2011] Scheme C, Step a: 1-(2-(1-Piperidinyl)ethyl)-4-piperidone

[2012] 1-(2-(1-Piperidinyl)ethyl)-4-piperidone is prepared from4-piperidone and 1-(2-chloroethyl)piperidine essentially as describedabove in Example 38, Scheme C, step a.

[2013] Scheme C, Step b: 1-(2-(1-Piperidinyl)ethyl)-4-piperidone Oxime

[2014] 1-(2-(1-Piperidinyl)ethyl)-4-piperidone oxime is prepared from1-(2-(1-piperidinyl)ethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[2015] Scheme C, Step c: 4-Amino-1-(2-(1-piperidinyl)ethyl)piperidine

[2016] 4-Amino-1-(2-(1-piperidinyl)ethyl)piperidine is prepared from1-(2-(1-piperidinyl)ethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2017] Scheme A, Step b:2-Chloro-6-[4-(1-(2-(1-piperidinyl)ethyl)piperidinylamino]-9-cyclopentylpurine

[2018]2-Chloro-6-[4-(1-(2-(1-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-(1-piperidinyl)ethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2019] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2020]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-(1-piperidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1352-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2021] Preparation of 4-Amino-1-(2-(4-morpholinyl)ethyl)piperidine

[2022] Method 1

[2023] Scheme B, Step a:4-Carboxamide-1-(2-(4-morpholinyl)ethyl)piperidine

[2024] 4-Carboxamide-1-(2-(4-morpholinyl)ethyl)piperidine may beprepared from isonipecotamide and 1-(2-chloroethyl)morpholineessentially as described above in Example 38, Scheme B, step a.

[2025] Scheme B, Step b: 4-Amino-1-(2-(4-morpholinyl)ethyl)piperidine

[2026] 4-Amino-1-(2-(4-morpholinyl)ethyl)piperidine is prepared from4-carboxamide-1-(2-(4-morpholinyl)ethyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2027] Method 2

[2028] Scheme C, Step a: 1-(2-(4-Morpholinyl)ethyl)-4-piperidone

[2029] 1-(2-(4-Morpholinyl)ethyl)-4-piperidone is prepared from4-piperidone and 1-(2-chloroethyl)morpholine essentially as describedabove in Example 38, Scheme C, step a.

[2030] Scheme C, Step b: 1-(2-(4-Morpholinyl)ethyl)-4-piperidone Oxime

[2031] 1-(2-(4-Morpholinyl)ethyl)-4-piperidone oxime is prepared from1-(2-(4-morpholinyl)ethyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[2032] Scheme C, Step c: 4-Amino-1-(2-(4-morpholinyl)ethyl)piperidine

[2033] 4-Amino-1-(2-(4-morpholinyl)ethyl)piperidine is prepared from1-(2-(4-morpholinyl)ethyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2034] Scheme A, Step b:2-Chloro-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2035]2-Chloro-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-(4-morpholinyl)ethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2036] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2037]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurinedi is prepared from2-chloro-6-[4-(1-(2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1362-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine

[2038] Preparation of 4-Amino-1-(3-(1-piperidinyl)propyl)piperidine

[2039] Method 1

[2040] Scheme B, Step a:4-Carboxamide-1-(3-(1-piperidinyl)propyl)piperidine

[2041] 4-Carboxamide-1-(3-(1-piperidinyl)propyl)piperidine may beprepared from isonipecotamide and 1-(3-chloropropyl)piperidineessentially as described above in Example 38, Scheme B, step a.

[2042] Scheme B, Step b: 4-Amino-1-(3-(1-piperidinyl)propyl)piperidine

[2043] 4-Amino-1-(3-(1-piperidinyl)propyl)piperidine is prepared from4-carboxamide-1-(3-(1-piperidinyl)propyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2044] Method 2

[2045] Scheme C, Step a: 1-(3-(1-Piperidinyl)propyl-4-piperidone

[2046] 1-(3-(1-Piperidinyl)propyl)-4-piperidone is prepared from4-piperidone and 1-(3-chloropropyl)piperidine essentially as describedabove in Example 38, Scheme C, step a.

[2047] Scheme C, Step b: 1-(3-(1-Piperidinyl)propyl)-4-piperidone Oxime

[2048] 1-(3-(1-Piperidinyl)propyl)-4-piperidone oxime is prepared from1-(3-(1-piperidinyl)propyl)-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[2049] Scheme C, Step c: 4-Amino-1-(3-(1-piperidinyl)propyl)piperidine

[2050] 4-Amino-1-(3-(1-piperidinyl)propyl)piperidine is prepared from1-(3-(1-piperidinyl)propyl)-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2051] Scheme A, Step b:2-Chloro-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine

[2052]2-Chloro-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-(1-piperidinyl)propyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2053] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurine

[2054]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3-(1-piperidinyl)propyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 137(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurine

[2055] Preparation of(R,S)-4-Amino-1-(3-(1-methylpiperidinyl)methyl)piperidine

[2056] Method 1

[2057] Scheme B, Step a:(R,S)-4-Carboxamide-1-(3-(1-methylpiperidinyl)methyl)piperidine

[2058] (R,S)-4-Carboxamide-1-(3-(1-methylpiperidinyl)methyl)piperidinemay be prepared from isonipecotamide and(R,S)-3-chloromethyl-1-methylpiperidine essentially as described abovein Example 38, Scheme B, step a.

[2059] Scheme B, Step b:(R,S)-4-Amino-1-(3-(1-methylpiperidinyl)methyl)piperidine

[2060] (R,S)-4-Amino-1-(3-(1-methylpiperidinyl)methyl)piperidine isprepared from(R,S)-4-carboxamide-1-(3-(1-methylpiperidinyl)methyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[2061] Method 2

[2062] Scheme C, Step a:(R,S)-1-(3-(1-Methylpiperidinyl)methyl)-4-piperidone

[2063] (R,S)-1-(3-(1-Methylpiperidinyl)methyl)-4-piperidone is preparedfrom 4-piperidone and (R,S)-3-chloromethyl-1-methylpiperidineessentially as described above in Example 38, Scheme C, step a.

[2064] Scheme C, Step b:(R,S)-1-(3-(1-Methylpiperidinyl)methyl)-4-piperidone Oxime

[2065] (R,S)-1-(3-(1-Methylpiperidinyl)methyl)-4-piperidone oxime isprepared from (R,S)-1-(3-(1-methylpiperidinyl)methyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[2066] Scheme C, Step c:(R,S)-4-Amino-1-(3-(1-methylpiperidinyl)methyl)piperidine

[2067] (R,S)-4-Amino-1-(3-(1-methylpiperidinyl)methyl)piperidine isprepared from (R,S)-1-(3-(1-methylpiperidinyl)methyl)-4-piperidone oximeessentially as described above in Example 38, Scheme C, step c.

[2068] Scheme A, Step b:(R,S)-2-Chloro-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurine

[2069](R,S)-2-Chloro-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-4-amino-1-(3-(1-methylpiperidinyl)methyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[2070] Scheme A, Step c:(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurine

[2071](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurineis prepared from(R,S)-2-chloro-6-[4-(1-(3-(1-methyl)piperidinyl)methyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 138

[2072](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2073] Preparation of(R,S)-4-Amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine

[2074] Method 1

[2075] Scheme B, Step a:(R,S)-4-Carboxamide-1-(2-(3-(1-Methylpyrrolidinyl)ethyl)piperidine

[2076](R,S)-4-Carboxamide-1-(2-(3-(1-methylpyrrolidinyl)ethyl)piperidine maybe prepared from isonipecotamide and(R,S)-3-(2-chloroethyl)-1-methylpyrrolidine essentially as describedabove in Example 38, Scheme B, step a.

[2077] Scheme B, Step b:(R,S)-4-Amino-1-(2-(3-(1-methylpyrrolidinyl)ethyl)piperidine

[2078] (R,S)-4-Amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine isprepared from(R,S)-4-carboxamide-1-(2-(3-(1-methylpyrrolidinyl)ethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[2079] Method 2

[2080] Scheme C, Step a:(R,S)-1-(2-(3-(1-Methylpyrrolidinyl)ethyl)-4-piperidone

[2081] (R,S)-1-(2-(3-(1-Methylpyrrolidinyl)ethyl)-4-piperidone isprepared from 4-piperidone and(R,S)-3-(2-chloroethyl)-1-methylpyrrolidine essentially as describedabove in Example 38, Scheme C, step a.

[2082] Scheme C, Step b:(R,S)-1-(2-(3-(1-Methylpyrrolidinyl)ethyl)-4-piperidone Oxime

[2083] (R,S)-1-(2-(3-(1-Methylpyrrolidinyl)ethyl)-4-piperidone oxime isprepared from (R,S)-1-(2-(3-(1-methylpyrrolidinyl)ethyl)-4-piperidoneand hydroxylamine hydrochloride essentially as described above inExample 38, Scheme C, step b.

[2084] Scheme C, Step c:(R,S)-4-Amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine

[2085] (R,S)-4-Amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine isprepared from (R,S)-1-(2-(3-(1-methylpyrrolidinyl)ethyl)-4-piperidoneoxime essentially as described above in Example 38, Scheme C, step c.

[2086] Scheme A, Step b:(R,S)-2-Chloro-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2087](R,S)-2-Chloro-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-4-amino-1-(2-(3-(1-methylpyrrolidinyl))ethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[2088] Scheme A, Step c:(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2089](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from(R,S)-2-chloro-6-[4-(1-(2-(3-(1-methyl)pyrrolidinyl)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1392-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2090] Preparation of4-Amino-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine

[2091] Method 1

[2092] Scheme B, Step a:4-Carboxamide-1-(2-(1-(4-methylpiperazinyl)ethyl)piperidine

[2093] 4-Carboxamide-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine maybe prepared from isonipecotamide and1-(2-chloroethyl)-4-methylpiperazine essentially as described above inExample 38, Scheme B, step a.

[2094] Scheme B, Step b:4-Amino-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine

[2095] 4-Amino-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine isprepared from4-carboxamide-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine essentiallyas described above in Example 38, Scheme B, step b.

[2096] Method 2

[2097] Scheme C, Step a:1-(2-(1-(4-Methylpiperazinyl))ethyl)-4-piperidone

[2098] 1-(2-(1-(4-Methylpiperazinyl))ethyl-4-piperidone is prepared from4-piperidone and 1-(2-chloroethyl)-4-methylpiperazine essentially asdescribed above in Example 38, Scheme C, step a.

[2099] Scheme C, Step b:1-(2-(1-(4-Methylpiperazinyl))ethyl)-4-piperidone Oxime

[2100] 1-(2-(1-(4-Methylpiperazinyl))ethyl)-4-piperidone oxime isprepared from 1-(2-(1-(4-methylpiperazinyl))ethyl)-4-piperidone andhydroxylamine hydrochloride essentially as described above in Example38, Scheme C, step b.

[2101] Scheme C, Step c:4-Amino-1-(2-(1-)4-methylpiperazinyl))ethyl)piperidine

[2102] 4-Amino-1-(2-(1-(4-methylpiperazinyl)ethyl)piperidine is preparedfrom 1-(2-(1-(4-methylpiperazinyl))ethyl)-4-piperidone oxime essentiallyas described above in Example 38, Scheme C, step c.

[2103] Scheme A, Step b:2-Chloro-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2104]2-Chloro-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-(1-(4-methylpiperazinyl))ethyl)piperidine, andtriethylamine essentially as described above in Example 1, Scheme A,step b.

[2105] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurine

[2106]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-(1-(4-methyl)piperazinyl)ethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 140(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurine

[2107] Preparation of(R,S)-4-Amino-1-(2-phenyl-2-hydroxyethyl)piperidine

[2108] Method 1

[2109] Scheme B, Step a:(R,S)-4-Carboxamide-1-(2-phenyl-2-hydroxyethyl)piperidine

[2110] (R,S)-4-Carboxamide-1-(2-phenyl-2-hydroxyethyl)piperidine may beprepared from isonipecotamide and (R,S)-1-hydroxy-2-chloroethylbenzeneessentially as described above in Example 38, Scheme B, step a.

[2111] Scheme B, Step b:(R,S)-4-Amino-1-(2-phenyl-2-hydroxyethyl)piperidine

[2112] (R,S)-4-Amino-1-(2-phenyl-2-hydroxyethyl)piperidine is preparedfrom (R,S)-4-carboxamide 1-(2-phenyl-2-hydroxyethyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[2113] Method 2

[2114] Scheme C, Step a: (R,S)-1-(2-Phenyl-2-hydroxyethyl)-4-piperidone

[2115] (R,S)-1-(2-Phenyl-2-hydroxyethyl)-4-piperidone is prepared from4-piperidone and (R,S)-1-hydroxy-2-chloroethylbenzene essentially asdescribed above in Example 38, Scheme C, step a.

[2116] Scheme C, Step b: (R,S)-1-(2-Phenyl-2-hydroxyethyl)-4-piperidoneOxime

[2117] (R,S)-1-(2-Phenyl-2-hydroxyethyl)-4-piperidone oxime is preparedfrom (R,S)-1-(2-phenyl-2-hydroxyethyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[2118] Scheme C, Step c:(R,S)-4-Amino-1-(2-phenyl-2-hydroxyethyl)piperidine

[2119] (R,S)-4-Amino-1-(2-phenyl-2-hydroxyethyl)piperidine is preparedfrom (R,S)-1-(2-phenyl-2-hydroxyethyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, step c.

[2120] Scheme A, Step b:(R,S)-2-Chloro-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurine

[2121](R,S)-2-Chloro-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-4-amino-1-(2-phenyl-2-hydroxyethyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2122] Scheme A, Step c:(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurine

[2123](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurinedi is prepared from(R,S)-2-chloro-6-[4-(1-(2-phenyl-2-hydroxyethyl))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1412-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurine

[2124] Preparation of 4-Amino-(3,4-methylenedioxybenzyl)piperidine

[2125] Method 1

[2126] Scheme B, Step a:4-Carboxamide-1-(3,4-methylenedioxybenzyl)piperidine

[2127] 4-Carboxamide-1-(3,4-methylenedioxybenzyl)piperidine may beprepared from isonipecotamide and 5-chloromethyl-1,3-benzodioxoleessentially as described above in Example 38, Scheme B, step a.

[2128] Scheme B, Step b: 4-Amino-(3,4-methylenedioxybenzyl)piperidine

[2129] 4-Amino-(3,4-methylenedioxybenzyl)piperidine is prepared from4-carboxamide-1-(3,4-methylenedioxybenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2130] Method 2

[2131] Scheme C, Step a: 1-(3,4-Methylenedioxy)benzyl-4-piperidone

[2132] 1-(3,4-Methylenedioxy)benzyl-4-piperidone is prepared from4-piperidone and 5-chloromethyl-1,3-benzodioxole essentially asdescribed above in Example 38, Scheme C, step a.

[2133] Scheme C, Step b: 1-(3,4-Methylenedioxy)benzyl-4-piperidone Oxime

[2134] 1-(3,4-Methylenedioxy)benzyl-4-piperidone oxime is prepared from1-(3,4-methylenedioxy)benzyl-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[2135] Scheme C, Step c: 4-Amino-(3,4-methylenedioxybenzyl)piperidine

[2136] 4-Amino-(3,4-methylenedioxybenzyl)piperidine is prepared from1-(3,4-methylenedioxy)benzyl-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2137] Scheme A, Step b:2-Chloro-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurine

[2138]2-Chloro-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-(3,4-methylenedioxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2139] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurine

[2140]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(3,4-methylenedioxybenzyll))piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1422-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-benzimidazolinyl)ethyl)piperidinylamino]-9-cyclopentylpurine

[2141] Preparation of 4-Amino-1-(2-benzimidazolinyl)methylpiperidine

[2142] Method 1

[2143] Scheme B, Step a:4-Carboxamide-1-(2-benzimidazolinyl)methylpiperidine

[2144] 4-Carboxamide-1-(2-benzimidazolinyl)methylpiperidine may beprepared from isonipecotamide and 2-(chloromethyl)benzimidazoleessentially as described above in Example 38, Scheme B, step a.

[2145] Scheme B, Step b: 4-Amino-1-(2-benzimidazolinyl)methylpiperidine

[2146] 4-Amino-1-(2-benzimidazolinyl)methylpiperidine is prepared from4-carboxamide-1-(2-benzimidazolinyl)methylpiperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2147] Method 2

[2148] Scheme C, Step a: 1-(2-Benzimidazolyl)methyl-4-piperidone

[2149] 1-(2-Benzimidazolyl)methyl-4-piperidone is prepared from4-piperidone and 2-(chloromethyl)benzimidazole essentially as describedabove in Example 38, Scheme C, step a.

[2150] Scheme C, Step b: 1-(2-Benzimidazolyl)methyl-4-piperidone Oxime

[2151] 1-(2-Benzimidazolyl)methyl-4-piperidone oxime is prepared from1-(2-benzimidazolyl)methyl-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[2152] Scheme C, Step c: 4-Amino-1-(2-benzimidazolinyl)methylpiperidine

[2153] 4-Amino-1-(2-benzimidazolinyl)methylpiperidine is prepared from1-(2-benzimidazolyl)methyl-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2154] Scheme A, Step b:2-Chloro-6-[4-(1-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2155]2-Chloro-6-[4-(1-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-benzimidazolinyl)methylpiperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2156] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2157]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-benzimidazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1432-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2158] Preparation of4-Amino-1-(4-(2-methylthiazolinyl)methyl)piperidine

[2159] Method 1

[2160] Scheme B, Step a:4-Carboxamide-1-(4-(2-methylthiazolinyl))methylpiperidine

[2161] 4-Carboxamide-1-(4-(2-methylthiazolinyl))methylpiperidine may beprepared from isonipecotamide and 2-methyl-5-(chloromethyl)thiazoleessentially as described above in Example 38, Scheme B, step a.

[2162] Scheme B, Step b:4-Amino-1-(4-(2-methylthiazolinyl)methyl)piperidine

[2163] 4-Amino-1-(4-(2-methylthiazolinyl)methyl)piperidine is preparedfrom 4-carboxamide-1-(4-(2-methylthiazolinyl))methylpiperidineessentially as described above in Example 38, Scheme B, step b.

[2164] Method 2

[2165] Scheme C, Step a: 1-(4-(2-Methylthiazolinyl)methyl-4-piperidone

[2166] 1-(4-(2-Methylthiazolinyl)methyl)-4-piperidone is prepared from4-piperidone and 2-methyl-5-(chloromethyl)thiazole essentially asdescribed above in Example 38, Scheme C, step a.

[2167] Scheme C, Step b: 1-(4-(2-Methylthiazolinyl)methyl)-4-piperidoneOxime

[2168] 1-(4-(2-Methylthiazolinyl)methyl)-4-piperidone oxime is preparedfrom 1-(4-(2-methylthiazolinyl)methyl)-4-piperidone and hydroxylaminehydrochloride essentially as described above in Example 38, Scheme C,step b.

[2169] Scheme C, Step c:4-Amino-1-(4-(2-methylthiazolinyl)methyl)piperidine

[2170] 4-Amino-1-(4-(2-methylthiazolinyl)methyl)piperidine is preparedfrom 1-(4-(2-methylthiazolinyl)methyl)-4-piperidone oxime essentially asdescribed above in Example 38, Scheme C, Step c.

[2171] Scheme A, Step b:2-Chloro-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2172]2-Chloro-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-(2-methylthiazolinyl)methyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2173] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2174]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(4-(2-methyl)thiazolinyl)methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 1442-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2175] Preparation of 4-Amino-1-(2-thiopheneyl)methylpiperidine

[2176] Method 1

[2177] Scheme B, Step a: 4-Carboxamide-1-(2-thiopheneyl)methylpiperidine

[2178] 4-Carboxamide-1-(2-thiopheneyl)methylpiperidine may be preparedfrom isonipecotamide and 2-(chloromethyl)thiophene essentially asdescribed above in Example 38, Scheme B, step a.

[2179] Scheme B, Step b: 4-Amino-1-(2-thiopheneyl)methylpiperidine

[2180] 4-Amino-1-(2-thiopheneyl)methylpiperidine is prepared from4-carboxamide-1-(2-thiopheneyl)methylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[2181] Method 2

[2182] Scheme C, Step a: 1-(2-Thiopheneyl)methyl-4-piperidone

[2183] 1-(2-Thiopheneyl)methyl-4-piperidone is prepared from4-piperidone and 2-(chloromethyl)thiophene essentially as describedabove in Example 38, Scheme C, step a.

[2184] Scheme C, Step b: 1-(2-Thiopheneyl)methyl-4-piperidone Oxime

[2185] 1-(2-Thiopheneyl)methyl-4-piperidone oxime is prepared from1-(2-thiopheneyl)methyl-4-piperidone and hydroxylamine hydrochlorideessentially as described above in Example 38, Scheme C, step b.

[2186] Scheme C, Step c: 4-Amino-1-(2-thiopheneyl)methylpiperidine

[2187] 4-Amino-1-(2-thiopheneyl)methylpiperidine is prepared from1-(2-thiopheneyl)methyl-4-piperidone oxime essentially as describedabove in Example 38, Scheme C, step c.

[2188] Scheme A, Step b:2-Chloro-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2189]2-Chloro-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-thiopheneyl)methylpiperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2190] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurine

[2191]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurineis prepared from2-chloro-6-[4-(1-(2-thiopheneyl)methyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

EXAMPLE 145aTrans-2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurinedDihydrochloride

[2192] Scheme A, Step b:Trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine

[2193] Trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,trans-4-(amino)cyclohexanol, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[2194] Scheme A, Step c:Trans-2-[trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineDihydrochloride

[2195]Trans-2-[trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurinedihydrochloride is prepared fromtrans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2196] CIMS (NH₃) 414 (MH⁺)

[2197] Rf (min.)=3.25

EXAMPLE 145bCis-2-[Trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineDihydrochloride

[2198] Scheme A, Step b:Cis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine

[2199] Cis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,cis-4-(amino)cyclohexanol, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[2200] Scheme A, Step c:Cis-2-[trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurineDihydrochloride

[2201]Cis-2-[trans-(4-aminocyclohexyl)amino]-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurinedihydrochloride is prepared fromcis-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurinehydrochloride essentially as described in Example 1, Scheme A, step c.

[2202] CIMS (NH₃) 414 (MH⁺)

[2203] Rf (min.)=3.25

EXAMPLE 146(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurineDihydrochloride

[2204] Scheme A, Step b:(R,S)-2-Chloro-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurine

[2205](R,S)-2-Chloro-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,(R,S)-2-hydroxymethyl-1-aminocyclopentane, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2206] Scheme A, Step c:(R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurineDihydrochloride

[2207](R,S)-2-[Trans-(4-aminocyclohexyl)amino]-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurinedihydrochloride is prepared from(R,S)-2-chloro-6-[(1-hydroxymethyl)cyclopentylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2208] CIMS (NH₃) 414 (MH⁺)

[2209] Rf (min.)=3.27

EXAMPLE 1472-[Trans-(4-aminocyclohexyl)amino]-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurineDihydrochloride

[2210] Scheme A, Step b:2-Chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine

[2211] 2-Chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,2,4-dichlorophenylhydrazine, and triethylamine essentially as describedabove in Example 1, Scheme A, step b.

[2212] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurineDihydrochloride

[2213]2-[Trans-(4-aminocyclohexyl)amino]-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurinedihydrochloride is prepared from2-chloro-6-(2,4-dichlorophenylhydrazino)-9-cyclopentylpurine essentiallyas described in Example 1, Scheme A, step c.

[2214] CIMS (NH₃) 475 (MH⁺)

[2215] Rf (min.)=3.49

EXAMPLE 147-a2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2216] Scheme B, Step a: 4-Carboxamide-1-(1-naphthyl)methylpiperidine

[2217] 4-Carboxamide-1-(1-naphthyl)methylpiperidine may be prepared fromisonipecotamide and 1-(chloromethyl)naphthalene (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2218] Scheme B, Step b: 4-amino-1-(1-naphthyl)methylpiperidine

[2219] 4-Amino-1-(1-naphthyl)methylpiperidine is prepared from4-carboxamide-1-(1-naphthyl)methylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[2220] Scheme A, Step b:2-Chloro-6-[4-(1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine

[2221]2-Chloro-6-[4-1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(1-naphthyl)methylpiperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2222] Scheme A, step:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[(1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2223]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-(1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, Step c.

[2224] APCI: 539 (M⁺¹)

[2225] R_(f) (min.)=2.33

EXAMPLE 147-b2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2226] Scheme B, Step a:4-Carboxamide-1-(2-trifluoromethylbenzyl)piperidine

[2227] 4-Carboxamide-1-(2-trifluoromethylbenzyl)piperidine may beprepared from isonipecotamide and 2-(trifluoromethyl)benzyl bromide(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2228] Scheme B, Step b: 4-amino-1-(2-trifluoromethylbenzyl)piperidine

[2229] 4-Amino-1-(2-trifluoromethylbenzyl)piperidine is prepared from4-carboxamide-1-(2-trifluoromethylbenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2230] Scheme A, Step b:2-Chloro-6-[4-[1-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2231]2-Chloro-6-[4-[1-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-trifluoromethylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2232] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2233]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethylbenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2234] APCI: 557 (M⁺¹)

[2235] R_(f) (min.)=2.29

EXAMPLE 147-c2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2236] Scheme B, Step a:4-Carboxamide-1-(3,5-dimethoxylbenzyl)piperidine

[2237] 4-Carboxamide-1-(3,5-dimethoxybenzyl)piperidine may be preparedfrom isonipecotamide and 3,5-dimethoxybenzyl chloride (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2238] Scheme B, Step b: 4-amino-1-(3,5-dimethoxy)piperidine

[2239] 4-Amino-1-(3,5-dimethoxybenzyl)piperidine is prepared from4-carboxamide-1-(3,5-dimethoxybenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2240] Scheme A, Step b:2-Chloro-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine

[2241]2-Chloro-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,5-dimethoxybenzyl)-piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2242] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2243]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3,5-dimethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2244] APCI: 549 (M⁺¹)

[2245] R_(f) (min.)=2.27

EXAMPLE 147-d2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-[3,5-bis(trifluoromethyl)benzyl]]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2246] Scheme B, Step a:4-Carboxamide-1-(3,5-bis-trifluoromethylbenzyl)piperidine

[2247] 4-Carboxamide-1-(3,5-bis-trifluoromethylbenzyl)piperidine may beprepared from isonipecotamide and bis(3,5-trifluoromethyl)benzyl bromide(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2248] Scheme B, Step b:4-amino-1-(3,5-bis-trifluoromethylbenzyl)piperidine

[2249] 4-Amino-1-(3,5-bis-trifluoromethylbenzyl)piperidine is preparedfrom 4-carboxamide-1-(3,5-bis-trifluoromethylbenzyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[2250] Scheme A, Step b:2-Chloro-6-[4-[1-(3,5-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2251]2-Chloro-6-[4-[1-(3,5-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,5-bis-trifluoromethylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2252] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-bis-(trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2253]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-[3,5-bis(trifluoromethyl)benzyl]]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-bis(3,5-trifluoromethyl)benzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2254] APCI: 625 (M⁺¹)

[2255] R_(f) (min.)=2.37

EXAMPLE 147-e2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2256] Scheme B, Step a: 4-Carboxamide-1-(2,3-difluorobenzyl)piperidine

[2257] 4-Carboxamide-1-(2,3-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,3-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2258] Scheme B, Step b: 4-amino-1-(2,3-difluorobenzyl)piperidine

[2259] 4-Amino-1-(2,3-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(2,3-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2260] Scheme A, Step b:2-Chloro-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2261]2-Chloro-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,3-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2262] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2263]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,3-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2264] APCI: 525 (M⁺¹)

[2265] R_(f) (min.)=2.26

EXAMPLE 147-f2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2266] Scheme B, Step a: 4-Carboxamide-1-(2,5-difluorobenzyl)piperidine

[2267] 4-Carboxamide-1-(2,5-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,5-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2268] Scheme B, Step b: 4-amino-1-(2,5-difluorobenzyl)piperidine

[2269] 4-Amino-1-(2,5-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(2,5-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2270] Scheme A, Step b:2-Chloro-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2271]2-Chloro-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,5-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2272] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2273]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2274] APCI: 525 (M⁺¹)

[2275] R_(f) (min.)=2.26

EXAMPLE 147-g2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2276] Scheme B, Step a: 4-Carboxamide-1-(3,5-difluorobenzyl)piperidine

[2277] 4-Carboxamide-1-(3,5-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 3,5-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2278] Scheme B, Step b: 4-amino-1-(3,5-difluorobenzyl)piperidine

[2279] 4-Amino-1-(3,5-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(3,5-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2280] Scheme A, Step b:2-Chloro-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2281]2-Chloro-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,5-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2282] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2283]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3,5-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2284] APCI: 525 (M⁻¹)

[2285] R_(f) (min.)=2.25

EXAMPLE 147-h2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2286] Scheme B, Step a: 4-Carboxamide-1-(2,4-difluorobenzyl)piperidine

[2287] 4-Carboxamide-1-(2,4-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,4-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2288] Scheme B, Step b: 4-amino-1-(2,4-difluorobenzyl)piperidine

[2289] 4-Amino-1-(2,4-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(2,4-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2290] Scheme A, Step b:2-Chloro-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2291]2-Chloro-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,4-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2292] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2293]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2294] APCI: 525 (M⁺¹)

[2295] R_(f) (min.)=2.25

EXAMPLE 147-i2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2296] Scheme B, Step a: 4-Carboxamide-1-(3-methylbenzyl)piperidine

[2297] 4-Carboxamide-1-(3-methylbenzyl)piperidine may be prepared fromisonipecotamide and 3-methylbenzyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2298] Scheme B, Step b: 4-amino-1-(3-methylbenzyl)piperidine

[2299] 4-Amino-1-(3-methylbenzyl)piperidine is prepared from4-carboxamide-1-(3-methylbenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2300] Scheme A, Step b:2-Chloro-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2301]2-Chloro-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-methylbenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2302] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2303]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2304] APCI: 503 (M⁺¹)

[2305] R_(f) (min.)=2.24

EXAMPLE 147-i2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2306] Scheme B, Step a: 4-Carboxamide-1-(3-fluorobenzyl)piperidine

[2307] 4-Carboxamide-1-(3-fluorobenzyl)piperidine may be prepared fromisonipecotamide and 3-fluorobenzyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2308] Scheme B, Step b: 4-amino-1-(3-fluorobenzyl)piperidine

[2309] 4-Amino-1-(3-fluorobenzyl)piperidine is prepared from4-carboxamide-1-(3-fluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2310] Scheme A, Step b:2-Chloro-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2311]2-Chloro-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-fluorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2312] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2313]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2314] APCI: 507 (M⁺¹)

[2315] R_(f) (min.)=2.25

EXAMPLE 147-k2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2316] Scheme B, Step a: 4-Carboxamide-1-(2-fluorobenzyl)piperidine

[2317] 4-Carboxamide-1-(2-fluorobenzyl)piperidine may be prepared fromisonipecotamide and 2-fluorobenzyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2318] Scheme B, Step b: 4-amino-1-(2-fluorobenzyl)piperidine

[2319] 4-Amino-1-(2-fluorobenzyl)piperidine is prepared from4-carboxamide-1-(2-fluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2320] Scheme A, Step b:2-Chloro-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2321]2-Chloro-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-fluorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2322] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2323]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2324] APCI: 507 (M⁻¹)

[2325] R_(f) (min.)=2.22

EXAMPLE 147-l2-[Trans-(4-aminocyclohexyl)amino]-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2326] Scheme B, Step a: 4-Carboxamide-1-(4-fluorobenzyl)piperidine

[2327] 4-Carboxamide-1-(4-fluorobenzyl)piperidine may be prepared fromisonipecotamide and 4-fluorobenzyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2328] Scheme B, Step b: 4-amino-1-(4-fluorobenzyl)piperidine

[2329] 4-Amino-1-(4-fluorobenzyl)piperidine is prepared from4-carboxamide-1-(4-fluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2330] Scheme A, Step b:2-Chloro-6-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2331]2-Chloro-6-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4-fluorobenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b

[2332] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2333]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2334] APCI: 507 (M⁺¹)

[2335] R_(f) (min.)=2.23

EXAMPLE 147-m2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2336] Scheme B, Step a:4-Carboxamide-1-(3-trifluoromethylbenzyl)piperidine

[2337] 4-Carboxamide-1-(3-trifluoromethylbenzyl)piperidine may beprepared from isonipecotamide and 3-(trifluoromethyl)benzyl bromide(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2338] Scheme B, Step b: 4-amino-1-(3-trifluoromethylbenzyl)piperidine

[2339] 4-Amino-1-(3-trifluoromethylbenzyl)piperidine is prepared from4-carboxamide-1-(3-trifluoromethylbenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2340] Scheme A, Step b:2-Chloro-6-[4-[1-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2341]2-Chloro-6-[4-[1-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-trifluoromethylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2342] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2343]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-trifluoromethylbenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2344] APCI: 557 (M⁺¹)

[2345] R_(f) (min.)=2.31

EXAMPLE 147-n2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-6-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2346] Scheme B, Step a:4-Carboxamide-1-(2-chloro-6-fluorobenzyl)piperidine

[2347] 4-Carboxamide-1-(2-chloro-6-fluorobenzyl)piperidine may beprepared from isonipecotamide and 2-chloro-6-fluorobenzyl chloride(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2348] Scheme B, Step b: 4-amino-1-(2-chloro-6-fluorobenzyl)piperidine

[2349] 4-Amino-1-(2-chloro-6-fluorobenzyl)piperidine is prepared from4-carboxamide-1-(2-chloro-6-fluorobenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2350] Scheme A, Step b:2-Chloro-6-[4-[1-(2-chloro-6-fluorobenzyl)piperidinylamino]-9-cyclopentylpurine

[2351]2-Chloro-6-[4-[1-(2-chloro-6-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-chloro-6-fluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2352] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-6-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2353]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-6-fluorobenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-chloro-6-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2354] APCI: 541 (M⁺¹)

[2355] R_(f) (min.)=2.22

EXAMPLE 147-o2-[Trans-(4-aminocyclohexyl)amino]-4-[1-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2356] Scheme B, Step a: 4-Carboxamide-1-(3,4-dichlorobenzyl)piperidine

[2357] 4-Carboxamide-1-(3,4-dichlorobenzyl)piperidine may be preparedfrom isonipecotamide and 3,4-dichlorobenzyl chloride (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2358] Scheme B, Step b: 4-amino-1-(3,4-dichlorobenzyl)piperidine

[2359] 4-Amino-1-(3,4-dichlorobenzyl)piperidine is prepared from4-carboxamide-1-(3,4-dichlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2360] Scheme A, Step b:2-Chloro-6-[4-[1-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2361]2-Chloro-6-[4-[1-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,4-dichlorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2362] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,4-chlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2363]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2364] APCI: 557 (M⁺¹)

[2365] R_(f) (min.)=2.33

EXAMPLE 147-p2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2366] Scheme B, Step a: 4-Carboxamide-1-(2-naphthyl)methylpiperidine

[2367] 4-Carboxamide-1-(2-naphthyl)methylpiperidine may be prepared fromisonipecotamide and 2-(chloromethyl)naphthalene (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2368] Scheme B, Step b: 4-amino-1-(2-naphthyl)methylpiperidine

[2369] 4-Amino-1-(2-naphthyl)methylpiperidine is prepared from4-carboxamide-1-(2-naphthyl)methylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[2370] Scheme A, Step b:2-Chloro-6-[4-1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine

[2371]2-Chloro-6-[4-1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-naphthyl)methylpiperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2372] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2373]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-1-(2-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2374] APCI: 539 (M⁺¹)

[2375] R_(f) (min.)=2.30

EXAMPLE 147-q2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2376] Scheme B, Step a: 4-Carboxamide-1-(2-methoxybenzyl)piperidine

[2377] 4-Carboxamide-1-(2-methoxybenzyl)piperidine may be prepared fromisonipecotamide and 2-methoxybenzyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2378] Scheme B, Step b: 4-amino-1-(2-methoxybenzyl)piperidine

[2379] 4-Amino-1-(2-methoxybenzyl)piperidine is prepared from4-carboxamide-1-(2-methoxybenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2380] Scheme A, Step b:2-Chloro-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurine

[2381]2-Chloro-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-methoxybenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2382] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2383]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-methoxybenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2384] APCI: 519 (M⁺¹)

[2385] R_(f) (min.)=2.19

EXAMPLE 147-r2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2386] Scheme B, Step a: 4-Carboxamide-1-(2,5-dichlorobenzyl)piperidine

[2387] 4-Carboxamide-1-(2,5-dichlorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,5-dichlorobenzyl chloride (available fromLancaster) essentially as described above in Example 38, Scheme B, stepa.

[2388] Scheme B, Step b: 4-amino-1-(2,5-dichlorobenzyl)piperidine

[2389] 4-Amino-1-(2,5-dichlorobenzyl)piperidine is prepared from4-carboxamide-1-(2,5-dichlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2390] Scheme A, Step b:2-Chloro-6-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2391]2-Chloro-6-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,5-dichlorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2392] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2393]2-[Trans-(4-aminocyclohexyl)amino]-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2394] APCI: 557 (M⁺¹)

[2395] R_(f) (min.)=2.22

EXAMPLE 147-s2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2396] Scheme B, Step a: 4-Carboxamide-1-cyclohexylmethylpiperidine

[2397] 4-Carboxamide-1-cyclohexylmethylpiperidine may be prepared fromisonipecotamide and cyclohexylmethyl bromide (available from AldrichChemical Company) essentially as described above in Example 38, SchemeB, step a.

[2398] Scheme B, Step b: 4-amino-1-cyclohexylmethylpiperidine

[2399] 4-Amino-1-cyclohexylmethylpiperidine is prepared from4-carboxamide-1-cyclohexylmethylpiperidine essentially as describedabove in Example 38, Scheme B, step b.

[2400] Scheme A, Step b:2-Chloro-6-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurine

[2401]2-Chloro-6-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-cyclohexylmethylpiperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2402] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2403]2-[Trans-(4-aminocyclohexyl)amino]-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-(1-cyclohexylmethyl)piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2404] APCI: 495 (M⁺¹)

[2405] R_(f) (min.)=2.25

EXAMPLE 147-t2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2406] Scheme B, Step a:4-Carboxamide-1-(2-chloro-4-fluorobenzyl)piperidine

[2407] 4-Carboxamide-1-(2-chloro-4-fluorobenzyl)piperidine may beprepared from isonipecotamide and 2-chloro-4-fluorobenzyl chloride(available from Lancaster or Acros) essentially as described above inExample 38, Scheme B, step a.

[2408] Scheme B, Step b: 4-amino-1-(2-chloro-4-fluorobenzyl)piperidine

[2409] 4-Amino-1-(2-chloro-4-fluorobenzyl)piperidine is prepared from4-carboxamide-1-(2-chloro-4-fluorobenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2410] Scheme A, Step b:2-Chloro-6-[4-[1-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2411]2-Chloro-6-[4-[1-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-chloro-4-fluorobenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2412] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2413]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-chloro-4-fluorobenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-chloro-4-fluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2414] APCI: 541 (M⁺¹)

[2415] R_(f) (min.)=2.28

EXAMPLE 147-u2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2416] Scheme B, Step a: 4-Carboxamide-1-(3,4-difluorobenzyl)piperidine

[2417] 4-Carboxamide-1-(3,4-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 3,4-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2418] Scheme B, Step b: 4-amino-1-(3,4-difluorobenzyl)piperidine

[2419] 4-Amino-1-(3,4-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(3,4-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2420] Scheme A, Step b:2-Chloro-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2421]2-Chloro-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,4-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2422] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2423]2-[Trans-4-aminocyclohexyl)amino]-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3,4-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2424] APCI: 525 (M⁺¹)

[2425] R_(f) (min.)=2.29

EXAMPLE 147-v2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2426] Scheme B, Step a: 4-Carboxamide-1-(2,6-difluorobenzyl)piperidine

[2427] 4-Carboxamide-1-(2,6-difluorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,6-difluorobenzyl bromide (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2428] Scheme B, Step b: 4-amino-1-(2,6-difluorobenzyl)piperidine

[2429] 4-Amino-1-(2,6-difluorobenzyl)piperidine is prepared from4-carboxamide-1-(2,6-difluorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2430] Scheme A, Step b:2-Chloro-6-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2431]2-Chloro-6-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,6-difluorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2432] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2433]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,6-difluorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2434] APCI: 525 (M⁺¹)

[2435] R_(f) (min.)=2.26

EXAMPLE 147-w2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2436] Scheme B, Step a: 4-Carboxamide-1-(3,5-dichlorobenzyl)piperidine

[2437] 4-Carboxamide-1-(3,5-dichlorobenzyl)piperidine may be preparedfrom isonipecotamide and 3,5-dichlorobenzyl chloride (available fromTrans World Chemicals or Fluorochem Ltd.) essentially as described abovein Example 38, Scheme B, step a.

[2438] Scheme B, Step b: 4-amino-1-(3,5-dichlorobenzyl)piperidine

[2439] 4-Amino-1-(3,5-dichlorobenzyl)piperidine is prepared from4-carboxamide-1-(3,5-dichlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2440] Scheme A, Step b:2-Chloro-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurine

[2441]2-Chloro-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3,5-dichlorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2442] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2443]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3,5-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2444] APCI: 557 (M⁺¹)

[2445] R_(f) (min.)=2.31

EXAMPLE 147-x2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2446] Scheme B, Step a: 4-Carboxamide-1-(2,4-dichlorobenzyl)piperidine

[2447] 4-Carboxamide-1-(2,4-dichlorobenzyl)piperidine may be preparedfrom isonipecotamide and 2,4-dichlorobenzyl chloride (available fromAldrich Chemical Company) essentially as described above in Example 38,Scheme B, step a.

[2448] Scheme B, Step b: 4-amino-1-(2,4-dichlorobenzyl)piperidine

[2449] 4-Amino-1-(2,4-dichlorobenzyl)piperidine is prepared from4-carboxamide-1-(2,4-dichlorobenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2450] Scheme A, Step b:2-Chloro-6-[4-[1-(2,4-dichlorobenzyl)piperidinylamino]-9-cyclopentylpurine

[2451]2-Chloro-6-[4-[1-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,4-dichlorobenzyl)piperidine, and triethylamine essentiallyas described above in Example 1, Scheme A, step b.

[2452] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2453]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,4-dichlorobenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2454] APCI: 557 (M⁺¹)

[2455] R_(f) (min.)=2.31

EXAMPLE 147-v2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2456] Scheme B, Step a:4-Carboxamide-1-(3-chloro-4-methylbenzyl)piperidine

[2457] 4-Carboxamide-1-(3-chloro-4-methylbenzyl)piperidine may beprepared from isonipecotamide and 3-chloro-4-methylbenzyl chloride(available from Pfaltz-Bauer) essentially as described above in Example38, Scheme B, step a.

[2458] Scheme B, Step b: 4-amino-1-(3-chloro-4-methylbenzyl)piperidine

[2459] 4-Amino-1-(3-chloro-4-methylbenzyl)piperidine is prepared from4-carboxamide-1-(3-chloro-4-methylbenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2460] Scheme A, Step b:2-Chloro-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2461]2-Chloro-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-chloro-4-methylbenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2462] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-CyclopentylpurineTrihydrochloride

[2463]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3-chloro-4-methylbenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2464] APCI: 537 (M⁺¹)

[2465] R_(f) (min.)=2.25

EXAMPLE 147-z2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2466] Scheme B, Step a:4-Carboxamide-1-(4-trifluoromethoxybenzyl)piperidine

[2467] 4-Carboxamide-1-(4-trifluoromethoxybenzyl)piperidine may beprepared from isonipecotamide and 4-(trifluoromethoxy)benzyl bromide(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2468] Scheme B, Step b: 4-amino-1-(4-trifluoromethoxybenzyl)piperidine

[2469] 4-Amino-1-(4-trifluoromethoxybenzyl)piperidine is prepared from4-carboxamide-1-(4-trifluoromethoxybenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2470] Scheme A, Step b:2-Chloro-6-[4-[1-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine

[2471]2-Chloro-6-[4-[1-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(4trifluoromethoxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2472] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2473]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(4-trifluoromethoxybenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(4-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2474] APCI: 573 (M⁺¹)

[2475] R_(f) (min.)=2.23

EXAMPLE 147-aa2-[Trans-4-aminocyclohexyl)amino]-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2476] Scheme B, Step a:4-Carboxamide-1-(2,4-bis-trifluoromethylbenzyl)piperidine

[2477] 4-Carboxamide-1-(2,4-bis-trifluoromethylbenzyl)piperidine may beprepared from isonipecotamide and bis(2,4-trifluoromethyl)benzyl bromide(available from Aldrich Chemical Company) essentially as described abovein Example 38, Scheme B, step a.

[2478] Scheme B, Step b:4-amino-1-(2,4-bis-trifluoromethylbenzyl)piperidine

[2479] 4-Amino-1-(2,4-bis-trifluoromethylbenzyl)piperidine is preparedfrom 4-carboxamide-1-(2,4-bis-trifluoromethylbenzyl)piperidineessentially as described above in Example 38, Scheme B, step b.

[2480] Scheme A, Step b:2-Chloro-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurine

[2481]2-Chloro-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2,4-bis-trifluoromethylbenzyl)]piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2482] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2483]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2,4-bis-trifluoromethylbenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2484] APCI: 625 (M⁺¹)

[2485] R_(f) (min.)=1.44

EXAMPLE 147-ab2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2486] Scheme B, Step a:4-Carboxamide-1-(2-trifluoromethoxybenzyl)piperidine

[2487] 4-Carboxamide-1-(2-trifluoromethoxybenzyl)piperidine may beprepared from isonipecotamide and 2-(trifluoromethoxy)benzyl bromide(available from Fluorochem Ltd.) essentially as described above inExample 38, Scheme B, step a.

[2488] Scheme B, Step b: 4-amino-1-(2-trifluoromethoxybenzyl)piperidine

[2489] 4-Amino-1-(2-trifluoromethoxybenzyl)piperidine is prepared from4-carboxamide-1-(2-trifluoromethoxybenzyl)piperidine essentially asdescribed above in Example 38, Scheme B, step b.

[2490] Scheme A, Step b:2-Chloro-6-[4-[1-(2-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurine

[2491]2-Chloro-6-[4-[1-(2-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(2-trifluoromethoxybenzyl)piperidine, and triethylamineessentially as described above in Example 1, Scheme A, step b.

[2492] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2493]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(2-trifluoromethoxybenzyl)]-piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(2-trifluoromethoxybenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2494] APCI: 573 (M⁺¹)

[2495] R_(f) (min.)=2.26

EXAMPLE 147-ac2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurineTrihydrochloride

[2496] N-Benzyl-4-(aminomethyl)piperidine

[2497] N-Benzyl-4-aminomethylpiperidine is prepared from4-(aminomethyl)piperidine (available from Aldrich Chemical Company) asdescribed by L. G. Humber [J. Med. Chem., 2, 441-443 (1966)]

[2498] Scheme A, Step b:2-Chloro-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurine

[2499]2-Chloro-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurine isprepared from 2,6-dichloro-9-cyclopentylpurine,N-benzyl-4-aminomethylpiperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2500] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurineTrihydrochloride

[2501]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-(1-benzyl)piperidinylmethylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2502] APCI: 503 (M⁺¹)

[2503] R_(f) (min.)=2.24

EXAMPLE 147-ad2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2504] Scheme B, Step a: 4-Carboxamide-1-(3-phenoxybenzyl)piperidine

[2505] 4-Carboxamide-1-(3-phenoxybenzyl)piperidine may be prepared fromisonipecotamide and 3-phenoxybenzyl chloride (available from Lancaster)essentially as described above in Example 38, Scheme B, step a.

[2506] Scheme B, Step b: 4-amino-1-(3-phenoxybenzyl)piperidine

[2507] 4-Amino-1-(3-phenoxybenzyl)piperidine is prepared from4-carboxamide-1-(4-phenoxybenzyl)piperidine essentially as describedabove in Example 38, Scheme B, step b.

[2508] Scheme A, Step b:2-Chloro-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurine

[2509]2-Chloro-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurineis prepared from 2,6-dichloro-9-cyclopentylpurine,4-amino-1-(3-phenoxybenzyl)piperidine, and triethylamine essentially asdescribed above in Example 1, Scheme A, step b.

[2510] Scheme A, Step c:2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurineTrihydrochloride

[2511]2-[Trans-(4-aminocyclohexyl)amino]-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurinetrihydrochloride is prepared from2-chloro-6-[4-[1-(3-phenoxybenzyl)]piperidinylamino]-9-cyclopentylpurineessentially as described in Example 1, Scheme A, step c.

[2512] APCI: 581 (M⁺¹)

[2513] R_(f) (min.)=2.35

[2514] The term “neoplastic disease state” as used herein refers to anabnormal state or condition characterized by uncontrolled proliferationNeoplastic disease states include leukemias, carcinomas andadenocarcinomas, sarcomas, melanomas, and mixed types of neoplasms.

[2515] Leukemias include, but are not limited to, acute lymphoblastic,chronic lymphocytic, acute myeloblastic and chronic myelocyticleukemias.

[2516] Carcinomas and adenocarcinomas include, but are not limited to,those of the cervis, breast, prostate, esophagus, stomach, smallintestines, colon, ovary and lungs.

[2517] Sarcomas include, but are not limited to, oesteromas,osteosarcoma, lipoma, lipsarcoma, hemangiomas and hemangiosarcoma.

[2518] Melanomas include, but are not limited to, amelanotic andmelanotic melanomas.

[2519] Mixed types of neoplasms include, but are not limited to,carcinosarcoma, lymphoid tissue type, folicullar reticulum, cell sarcomaand Hodgkins Disease.

[2520] The term “therapeutically effective amount” of a compound of theformula (I) refers to an amount which is effective, upon single ormultiple dose administration to the patient, in controlling the growthof the neoplasm or metastases of the neoplasm or preventing apoptosis. Atherapeutically effective amount of a compound of the formula will varyaccording to the age, weight, type of neoplasm to be treated, thecombination of other antineoplastic agents, and other criteria wellknown to those skilled in the art using standard clinical and laboratorytests and procedures. A therapeutically effective amount of a compoundof the formula will vary according to the type of cell susceptible toapoptosis, the location of the infarct, as well as the age, weight andother criteria well known to those skilled in the art.

[2521] The term “controlling the growth” of the neoplasm refers toslowing, interrupting, arresting or stopping the growth of the neoplasmor metastates of the neoplasm. The term “controlling the growth” of theneoplasm also refers to killing the neoplasia or metastates of theneoplasia.

[2522] An effective amount of a compound of the formula is that amountwhich is effective, upon single or multiple dose administration to apatient in providing an antineoplastic effect or in preventingapoptosis. An “antineoplastic effect” refers to the slowing,interrupting, preventing or destruction of further growth of neoplasticcells.

[2523] An effective antineoplastic amount of a compound of the formulacan be readily determined by an attending diagnostician, as one skilledin the art, by the use of known techniques and by observing resultsobtained under analogous circumstances. In determining the effectiveamount, a number of factors are considered by the attendingdiagnostician, including but not limited to, the species of mammal; itssize, age and general health; the specific disease involved; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular compound of the formula administered;the mode of administration; the bioavailability characteristics of thepreparation administered; the dose regimen selected; the use ofconcomitant medication; and other relevant circumstances.

[2524] A further embodiment of the present invention includes a methodfor the prophylactic treatment of a patient at risk of developing aneoplastic disease state comprising administering a prophylacticallyeffective antineoplastic amount of a compound of the formula The term “apatient at risk of developing a neoplastic disease state” refers to apatient who, because of an identified genetic predisposition toneoplasms, had or currently have neoplasms, exposure of carcinogenicagents, diet, age or has other risk factors associated with thedevelopment of neoplastic disease states. Preferred patients at risk ofdeveloping a neoplastic disease state include patients who are positivefor oncogenic viruses, are in remission from prior treatment ofneoplasm(s), use tobacco products or have previously been exposed tocarcinogens such as asbestos, or are positive for various neoplasticgenetic markers.

[2525] Oncogenic viruses are those viruses associated with cancers. Forexample, Rous sarcoma of chickens, Shope rabbit papilloma, murineleukemia viruses are animal viruses recognized as having a role indevelopment of various cancers. Human papillomavirus is associated withgenital cancer. Molluscum contagiosum virus is associated with molluscumcontagiosum tumors. The JC virus, a human papovirus, is associated withdisorders of reticulendothelial system such as leukemia and lymphoma.Human retroviruses such as human T-cell lymphotropic viruses (HTLV)types 1 and 2 are associated with some human leukemias and lymphomas.Human immunodeficiency viruses (HIV) types 1 and 2 are the causes ofAIDS. Epstein-Barr virus has been associated with various malignancies,including nasopharyngeal carcinoma, African Burkitt's lymphoma andlymphomas in immunosuppressed organ transplant recipients.

[2526] Genetic markers such as mutations, rearrangments and the like inBRCA 1, bcl-1/PRAD1, cyclin D1/CCND1, p16, cdk4, especially an Arg24Cysmutation, p16^(INK4a). Genetic markers are associated withpredispositions to various neoplasms. For example, alterations in theBRCA 1 gene are associated with a higher risk for breast and ovariancancer. Other genetic markers include alterations in the MMSC1 gene,which interracts with the MMCA1 brain and prostate cancer gene, in theCtIP gene, which is linked to the BRACA1 gene in breast and ovariancancer, binds to the BRCA1 gene and is linked to the E1A oncogenepathway, and in the MKK3 gene, which is a cell cycle control gene thatacts as a tumor supressor in lung cancer by activating apoptosis.Patients at risk of developing a neoplastic disease state also includepatients who overexpress various cell cycle proteins, including cdk4,cyclins B1 and E. Patients at risk of developing a neoplastic diseasestate include those with elevated levels of tumor markers. Known tumormarkers include prostate specific antigen (PSA) and plasma insulin-likegrowth factor-1 (IGF-1), which are markers for prostate cancer. Nuclearmatrix proteins (NMPs) are associated with the presence of cancer,particularly bladder and colon cancers.

[2527] An effective amount of a compound of the formula is expected tovary from about 25 nonograms per kilogram of body weight per day(ng/kg/day) to about 500 mg/kg/day. Preferred effective amounts of acompound of the formula is from about 1 μg/kg/day to about 500μg/kg/day. A more preferred amount of a compound of the formula is fromabout 1 μg/kg/day to about 50 μg/kg/day.

[2528] A compound of the formula may be administered in any form or modewhich makes the compound bioavailable in effective amounts. Compounds ofthe formula may be administered by oral or parental routes. Compounds ofthe formula may be administered orally, subcutaneously, intramuscularly,intravenously, transdermally, intranasally, rectally, ocularly and thelike. Oral administration is preferred. One skilled in the art ofpreparing pharmacuetical formulations may readily determine appropriateforms of a compound of the formula by determining particularcharacteristics of the compound, the disease to be treated, the stage ofthe disease, response of other patients and other relevantcircumstances.

[2529] A compound of the formula may be combined with carriers,excipients or other compounds to prepare compositions of a compound ofthe formula. A composition of the formula comprise a compound of theformula in admixture or otherwise in association with one or more inertcarriers. Compositions of the formula are useful, for example, asconvenient means of making bulk shipments, or for storing, a compound ofthe formula An inert carrier is a material which does not degrade orotherwise covalently react with a compound of the formula. An inertcarrier may be a solid, semi-solid or liquid material. Preferredcarriers are water, aqueous buffers, organic solvents andpharmaceutically acceptable carriers or excipients. Preferred aqueousbuffers provide a buffering range at which a compound of the formuladoes not degrade. Preferred buffering ranges are about pH 4 to about pH9. Preferred organic solvents are acetonitrile, ethyl acetate, hexane.

[2530] A pharmaceutical composition of a compound of the formulacomprises a compound of the formula in admixture or otherwise inassociation with one or more pharmaceutically acceptable carrier orexcipient. A pharmaceutically acceptable carrier or excipient may be asolid, semi-solid or liquid material which can serve as a vehicle ormedium for the compound of the formula. Suitable pharmaceuticallyacceptable carriers or excipients are well-known to those skilled in theart.

[2531] A pharmaceutical composition of a compound of the formula may beadapted for the route of administration. A preferred pharmaceuticalcomposition of a compound of the formula is a tablet, troche, capsule,elixir, syrup, wafer, chewing gum, suppository, solution or suspensionif the route of administration is oral, parental or topical.

[2532] A preferred oral pharmaceutical composition of a compound of theformula comprises a compound of the formula with an inert diluent orwith an edible carrier. Preferred forms of oral pharmaceuticalcompositions of a compound of the formula are tablets, troches,capsules, elixirs, syrups, wafers, chewing gum, solutions orsuspensions.

[2533] Preferred pharmaceutical compositions of a compound of theformula contain from about 4% to about 80% of the compound. Preferredpharmaceutical compositions contain an amount of the compound of theformula from about 50 μg to about 500 μg; more preferred pharmaceuticalcomposition contain an amount of the compound of the formula from about1 μg to about 200 μg.

[2534] A compound of the formula may be administered alone or in theform of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients.

[2535] The following abbreviations are used herein: mg, milligram; μg,microgram; ηg, nanogram; TEA, triethylyamine; mmol, millimole: mL,milliliter; C, Celsius; hr, hour; TLC, thin layer chromatography;CH₂CL₂, methylene chloride; MeOH, methanol; EtOH, ethanol; N, Normal;HCl, hydrogen chloride; TFA, trifluoroacetic acid, DIEA,diisopropylethylamine; RT PCR, reverse transcription polymerase chainreaction; HEPES, 4-(2-hydoxyethyl0-1-piperazine ethanesulfonic acid);MgCl₂, Magnesium chloride; EGTA, ethyleneglycol-bis(β-aminoethylether)-N,N,N′,N′-tetraacetic acid; EDTA,ethylenediaminetetraacetic acid; DTT, dithiothreitol; MOI, multiplicityof infection; NaF, Sodium flouride; BSA, bovine serum albumin; p.o.,oral(ly) i.v., intravenous(ly); s.c., subcutaneous(ly).

EXAMPLE 148 Cyclin-dependent Kinase 4 Assay

[2536] The IC₅₀values for cdk-4 inhibition were by the following method:

[2537] Substrate

[2538] Glutathione S-transferase-retinoblastoma fusion protein (GST-Rb)(Kaelin, W. G., Jr., et al., Cell 64: 521-532, 1991) was obtained fromDr. William Kaelin. GST-Rb was prepared by transformation of E. coliwith the plasmid pGEX-Rb (379-928). The transformed bacteria were grownovernight to saturation, then diluted in YT broth and incubated at 37°C. for 2 h. The protein was induced by incubation with 0.1 mMisopropylthioglycoside for 3 h. Following sedimentation bycentrifugation, the cells were lysed by sonication in STE buffer (0.1 mMNaCl, 10 mM Tris, pH 8.0, 1 mM EDTA) containing 10% sarkosyl.Particulate matter was removed by centrifugation and the lysate wasincubated with glutathione-Sepharose at 4° C. The beads were washed withkinase buffer and then quantitation of Coomassie blue-stained proteinsseparated by SDS-PAGE was performed using a protein standard of knownconcentration.

[2539] Expression of CDK4/Cyclin D1 in Insect Cells

[2540] Human cyclin-dependent kinase 4 (cdk4) was cloned by RT PCR usingdegenerate primers based on the published amino acid sequence(Matsushime, H, et al., Cell, 71: 323-334, 1992). The cDNA for humancyclin D1 was cloned by RT PCR using genomic DNA from MCF 7 cells. Thesequence was consistent with the published sequence (Xiong, Y., et al.,Cell 65: 691-699, 1991.). Both the cDNAs for cdk4 and cyclin D1 werecloned into pFastBac (Life Technologies) and recombinant Bacmid DNAcontaining the cDNAs was produced by site-specific transposition usingthe Bac-to-Bac Baculovirus expression system purchased from LifeTechnologies (catalog # 10359-016). Bacmid DNA was used to transfect Sf9insect cells to produce recombinant virus. Following plaque purificationof the virus, the viral preparations were amplified until high titerstocks were acheived. Optimum coexpression of the recombinant proteinswas determined to be acheived with an MOI of 0.1 for both cdk4 andcyclin D1 at 72 h post infection.

[2541] Lysates were prepared by lysis of Sf9 cells coinfected with cdk4and cyclin D1 in 50 mM HEPES, pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.1 mMphenylmethylsulfonyl fluoride, 5 μg/ml aprotinin, and 5 μg/ml leupeptinusing a PARR bomb under 500 p.s.i nitrogen pressure for 5 min at 4° C.Insoluble material was sedimented at 10,000×g for 20 min at 4° C.Glycerol was added to the supernatant to 10% and stored at −80° C. inaliquots.

[2542] Kinase Assay

[2543] Pre-wet Millipore Multiscreen 96-well filter plates (0.65 μmDurapore filters) with 200 μl kinase buffer (50 mM HEPES, pH 7.5, 10 mMMgCl₂, 1 mM EGTA). GST-Rb (0.5 μg) bound to glutathione-Sepharose beadsis added in 50 μl per well and the solution removed by application ofvacuum. The assay contains 50 mM HEPES, pH 7.5, 10 mM MgCl₂, 1 mM EDTA,1 mM DTT, 1 mM EGTA, 10 mM β-glycerophosphate, 0.1 mM sodiumorthovanadate, 0.1 mM NaF, 0.25% BSA, 10 μM ATP and 0.25 μCi of[γ³³P]-ATP. Add 0.1 μg cdk4/cyclin D1 (insect cell lysate) to initiateassay. Incubate 30 min at 37° C. Terminate reaction by filtration onMillipore Vacuum Manifold. Wash four times with TNEN (20 mM Tris, pH8.0, 100 mm Na Cl, 1 mM EDTA, 0.5% nonidet P-40). After drying theplates at room temperature, the filter plates were placed in adapterplates (Packard) and 40 μl of Microscint-O® (Packard) was added to eachwell. Top Seal A film was used to cover the plates before counting in aTop Count Scintillation Counter.

[2544] The results are provided in Table 1.

EXAMPLE 149 cdk-2 Inhibition Studies

[2545] The IC₅₀ values for CDK-2 inhibition were determined by thefollowing method:

Cyclin-Dependent Kinase 2 Assay

[2546] Substrate: GST-Rb as Described Above for cdk4/cyclin D1

[2547] Expression of CDK2/Cyclin E in Insect Cells

[2548] Recombinant baculoviruses for human cdk2 and cyclin E wereobtained from Dr. David Morgan at UC, Berkeley (Desai, D. et al. Molec.Biol. Cell, 3:571-582, 1992). Optimum coexpression in insect cells wasobtained at MOI's of 0.1 and 1.0 for cdk2 and cyclin E, respectively, at72 h post infection.

[2549] Kinase Assay

[2550] Assay conditions for cdk2/cyclin E were identical to those forcdk4/cyclin D1 including the substrate. The concentration of recombinantcdk2/cyclin E in the assay was 0.1 μg per 100 μl assay. Incubation wasfor 30 min at 30° C.

[2551] The results are provided in Table 1.

EXAMPLE 150 Cdk7/Cyclin H Assay Protocol

[2552] Substrate: Peptide Substrate H₂N-RRR(YSPTSPS)₄-COOH Based onSequence of CTD of RNA Polymerase II

[2553] Expression of CDK7/Cyclin H in Insect Cells

[2554] Human cdk7 was cloned by reverse transcription PCR. The sequencewas consistent with that reported by Tassan, J. P., et al., J. CellBiol. 127: 467-478, 1994 and Darbon, J. M. et al. Oncogene, 9:3127-3138, 1994. The cDNA for cyclin H was also cloned by reversetranscription PCR and the sequence was consistent with that reported byFisher & Morgan, Cell, 78: 713-724, 1994. Recombinant Bacmid DNA andviral stocks were prepared as described above for cdk4 and cyclin D1.Optimum coexpression was achieved at MOI's of 1 and 2 for cdk7 andcyclin H, respectively at 48 h post infection.

[2555] Kinase Assay

[2556] The assay measures the phosphorylation of a peptide substrate(based on the C-terminal domain of RNA polymerase II) bycyclin-dependent kinase 7 which is activated by cyclin H.[γ³³P]-phosphate is transferred from [γ³³P]-ATP to the peptide substrateby the enzyme. The assay is run in 96-well V-bottom plates, thenfollowing termination the reaction is transferred to 96-well MilliporeMultiscreen phosphocellulose filter plates. The peptide is retained onthe phosphocellulose membrane after washing with a phosphoric acidsolution.

[2557] Method

[2558] Enzyme assay is run in 96-well V-bottom plates in a total volumeof 100 μl. Assay contains 15 μM ATP, 0.5 μCi [γ³³P]-ATP, 50 mM Hepes, pH7.5, 10 mM MgCl₂, 1 mM EDTA, 1 mM DTT, 10 mM γ-glycerophosphate, 0.1 mMsodium orthovanadate, 0.1 mM NaF, 10 μM peptide substrate. To initiatethe assay, 0.125 ng cdk7 and cyclin H (insect cell lysate) is added.Incubation is for 5 min at 24° C. Reaction is terminated by addition of40 μl cold 300 mM phosphoric acid to each sample. Contents of V-bottomwells were then transferred to a Millipore 96-well phosphocellulosefilter plate. After sitting for 15 min at room temperature vacuum wasapplied to the filter plate and the wells were washed 4× with 100 μl ofcold 75 mM phosphoric acid. After removal of the underdrain assembly,filters were dried completely, placed in Multiscreen microplateadapters, and 40 μl of Micro-Scint O added to each well. Plates werecovered with Top-Seal A film and counted for 1.5 min using a Packard TopCount Scintillation Counter.

[2559] The results are provided in Table 1

EXAMPLE 151 CDK1/cyclin B [³³P] SPA Assay Protocol

[2560] Substrate

[2561] The assay uses a biotinylated substrate peptide(biotin-PKTPKKAKKL) derived from the in vitro p34^(cdc2) phosphorylationsite of histone H1.

[2562] Expression of Cdk1/Cyclin B1 in Insect Cells

[2563] Human cdk1 was cloned by reverse transcription PCR. The sequencewas consistent with that reported by Lee, M. G. and Nurse, P. Nature,327:31-33, 1987. The cDNA for cyclin H was also cloned by RT PCR and thesequence was consistent with that reported by Pines, J. and Hunter, T.,Cell 58: 833-846, 1989. Recombinant Bacmid DNA and viral stocks wereprepared as described above for cdk4 and cyclin D1. Optimum coexpressionwas achieved at an MOI of 0.1 for both cdk1 and cyclin B1 at 48 h postinfection.

[2564] Kinase Assay: p34^(cdc2) SPA [³³P] kinase enzyme assay kit waspurchased from Amersham Life Science (catalog # RPNQ0170) and theprotocol was performed as a 96-well format assay as suggested by themanufacturer. Each assay contained 50 mM Tris HCl, pH 8.0, 10 mM MgCl₂,0.1 mM Na₃VO₄ (sodium orthovanadate), 0.5 uM ATP, 0.2 μCi ³³P-ATP, 2 μMDTT and 0.75 uM biotinylated peptide and 3 μg cdk1/cyclin B insect celllysate in a total assay volume of 100 μl. Incubation was for 30 min at30° C. The reaction was terminated by addition of 200 uL of stop buffer(50 uM ATP, 5 mM EDTA, 0.1%(v/v) Triton X-100 in phosphate bufferedsaline),/streptavidin-coated SPA beads (2.5 mg/ml). The plate was leftat room temperature overnight then covered with a Packard TopSeal andcounted on a Packard TopCount. The IC₅₀ value was determined by fittingthe data into a sigmodial curve using GraphPad Prism software.

EXAMPLE 152 In Vitro Tumor Inhibition

[2565] In Vitro Proliferation Assay

[2566] The proliferation of tumor cells was measured using asulforhodamine B assay as described in Skehan, P., et al., J. Natl.Cancer Inst. 82: 1107-1112, 1990. Tumor cells were harvested withtrypsin-EDTA, cells that excluded trypan blue were counted, added to96-well plates and incubated overnight at 37° C. Drug was added to thewells following dilution in culture medium. Three days later, the mediumwas removed and replenished with medium containing fresh drug andincubated an additional 4 days. The cells were then fixed with 0.1 ml10% trichloroacetic acid for 60 min at 4° C. The plates were rinsed fivetimes with tap water, air-dried and stained for 30 min with 0.4%sulforhodamine B in 1% acetic acid and air-dried. Bound dye wassolubilized with 0.1 ml 10 mM Tris (pH 10.5) for 5 min and theabsorbance measured at 490 nm using a Titertek Multiscan MCC/340 platereader.

[2567] Alternatively, the CyQUANT cell proliferation assay was used toquantitate cell proliferation.

[2568] CyQUANT Cell Proliferation Assay

[2569] Alternatively, the CyQUANT cell proliferation assay was used toquantify tumor cell proliferation. Tumor cells were harvested withtrypsin-EDTA, cells that excluded trypan blue were counted, added to96-well plates and incubated overnight at 37° C. Drug was added to thewells following dilution in culture medium. Three days later the mediumwas removed and the plates frozen at −80° C. for at least 30 minutes.After thawing the plates, 200 μL of CyQUANT-GR in Cell Lysis Buffer(Molecular Probes # C-7026) was added to each well and incubated 3-5minutes at room temperature. Fluorescence of CyQUANT-GR was measured ona Molecular Devices Fmax fluorescence microplate reader (excitation 485nm, emission 530 nm).

[2570] Cell Lines

[2571] MCF7 is a human breast adenocarcinoma, hormone-dependent (HTB22);

[2572] MDA-MB-231 is a human breast adenocarcinoma, hormone-independent(HTB 26);

[2573] HT-29 is a human colon adenocarcinoma, moderatelywell-differentiated grade II (HTB 38);

[2574] HCT-15 is a human colon adenocarcinoma (CCL 225);

[2575] A549 is a human non-small cell lung carcinoma (CCL 185);

[2576] PC-3 is a human prostate adenocarcinoma, hormone-independent (CRL1435); and

[2577] DU 145 is a human prostate carcinoma, hormone-independent (HTB81).

[2578] All of the cell lines were obtained from American Type TissueCollection, with the ATCC accession number in parentheticals.

[2579] MCF-7, MDA-MB-435 and and MDA-MB-231 cells were grown in improvedminimum essential medium (Biofluids) without phenol red, supplementedwith 5% fetal bovine serum, 0.01 mg/ml gentamicin and 3 mM L-glutamine.All of the other cell lines were grown in RPMI 1640 medium (LifeTechnologies) supplemented with 5% fetal bovine serum, 0.01 mg/mlgentamicin and 3 mM L-glutamine.

[2580] The results are provided in Table 1. In vitro Tumor CellProliferation (IC₅₀, μM) CDK-2 CDK4 Inhibition Inhibition Breast ColonLung MDL IC₅₀ IC₅₀ MC MDA-MB- MDA-MB- HT- HCT- Colo- DMS- ProstateNumber Structure (μM) (μM) F-7 231 435 29 15 205 A549 114 PC-3 DU145Example 29

0.011 0.04 1.0 0.71 4.2* 3.6* 5.9* 6.0* 4.4* 4.2* 2.8* 4.6* 2.9* 2.6*2.6* 3.3* 3.2* 3.5* 3.0* 2.9* Example 10

0.016 0.013 1.6 1.4* 5.2* 1.6* 1.7* 1.3* 2.6* 1.3* 2.6* 1.5* 1.4* 1.1*1.0* 1.3* 2.6* Example 32

0.054 0.025 0.027 0.014 1.3 1.6 0.85* 0.68* 1.59* 1.39* 1.0* 1.1* 0.82*1.2* 0.37* 0.68* 0.61* 0.51* 1.2* 0.57* 0.39* 0.64* Example 15

0.016 (n = 1) 0.04 1.8* 3.8* 2.1* 2.1* 1.6* 1.7* 1.2* 3.1* 1.8* 1.9*1.4* 1.2* 1.8* 3.7* Example 8

0.030 0.048 0.030 0.022 6.6 3.2 0.2 1 0.9 8 0.88 1.2 1.3 1.4 4.5 3.50.80 1.1 0.80 0.89 0.98 0.63 0.88 1.2 Example 16

0.055 0.030 0.23 0.28 4.7* 4.1* 9.2* 7.6* 6.4* 6.3* 3.4* 7.1* 0.5* 6.2*4.8* 4.4* 8.2* 3.3* 2.5* 3.3* Example 145a

0.050 1.5 1.6 3.0* 2.9* 3.3* 3.8* 3.4* 2.3* 1.7* 1.6* 4.4* 4.8* 4.6*3.1* 1.9* 2.1* 3.9* 3.8* Example 13

0.050 2.9 0.9 5 2.0 2.2 2.6 3.1 3.4 2.0 7.1 1.7 1.7 1.0 1.4 1.9 1.3 0.991.7 Example 147-m

0.065 0.077 0.37 0.32* 0.33* 0.42* 0.56* 0.34* 0.35* 0.18* 0.17* 0.17*0.22* 0.29* 0.32* 0.25* 0.50* 0.32* 0.35* Example 34

0.080 1.2 0.80 2.3 3.5 3.4 5.8 3.4 6.0 7.7 13 3.4 4.8 4.2 4.5 1.0 2.02.7 4.3 Example 21

0.082 0.080 0.23 0.97 1.3* 1.3* 1.9* 2.3* 1.6* 1.7* 1.2* 1.1* 0.6* 1.0*1.1* 0.7* 1.3* 0.7* 0.7* 0.9* Example 14

0.100 (n = 1) 1.5 3.0* 2.7* 2.4* 1.4* 1.3* 2.3* 2.8* Example 11

0.10 8.9 5.8 5.0* 6.7* 13* 10* 6.5* 7.8* 6.5* 5.2* 4.5* 3.4* 6.8* 4.9*3.6* 3.6* 4.6* 4.7* Example 147-s

0.12 0.10 1.3 0.62 0.31* 0.33* 0.42* 0.43* 0.35* 0.33* 0.28* 0.23* 0.22*0.20 0.57* 0.30* 0.31* 0.37* 0.29* 0.27* Example 26

0.11 (n = 1) 0.53 0.52 14* 13* 23* 22* 18* 22* 13* 15* 13* 17* 17* 15*15* 8* 18* 13* Example 2

0.12 0.10 1.3 1.0 2.3* 2.5* 3.5* 5.5* 8.0* 8.2* 2.4* 2.5* 2.4* 4.1* 2.2*3.2* 4.6* 3.0* 1.7* 2.2* 1.8* 1.2* 1.4* 3.6* 3.0* 4.4* 2.5* 1.8* 2.2*1.3* 1.5* 2.3* 2.8* Example 1

0.120 0.081 2.0 2.7 1.7 1.2 1.6 1.4 1.5 1.5 1.6 2.4 2.5 0.97 0.90 1.10.86 0.96 1.0 1.4 1.5 Example 147-u

0.15 0.11 2.8 2.6 0.33* 0.36* 0.47* 0.48* 0.41* 0.33* 0.28* 0.22* 0.27*0.19* 0.62* 0.35* 0.35* 0.43* 0.30* 0.28* Example 52

0.19 0.74 1.4 1.1 1.0* 1.2* 2.1* 2.4* 1.6* 2.0* 1.5* 1.1* 0.57* 0.68*1.4* 0.63* 1.7* 2.1* 1.4* 1.5* Example 27

0.13 0.130 1.4 10* 6* 9.3* 7.2* 3.8* 5.2* 4.9* 4.6* 3.1* 1.6* 2.1* 2.1*2.6* 3.0* 5.0* 2.4* Example 147-q

0.11 0.24 0.08 0.69 1.3 0.19* 0.25* 0.36* 0.33* 0.32* 0.38* 0.17* 0.19*0.18* 0.19* 0.40* 0.21* 0.33* 0.40* 0.29* 0.32* Example 147-ae

0.140 (n = 1) 6.5* 6.6* 14* 11* 10* 10* 11* 8.6* 11* 11* 8.7* 11* 5.1*12* 6.7* Example 147-w

0.13 0.18 4.0 2.1 0.35* 0.40* 0.57* 0.51* 0.37* 0.39* 0.32* 0.32* 0.21*0.21* 0.45* 0.31* 0.44* 0.46* 0.35* 0.39* Example 7

0.160 (n = 1) 1.4 4.4* 4.9* 11* 10* 4.6* 4.8* 3.4* 3.5* 3.4* 3.4* 2.8*3.3* 4.2* 4.8* 5.5* 5.2* Example 146

0.164 1.6 0.81 0.50 14* 12* 18* 21* 16* 11* 12* 14* 12* 12* 13* 11* 11*10* 12* 16* Example 9

0.165 (n = 1) 3.9 2.0 0.7* 1.1* >10* >10* 0.87* 0.96* 0.76* 0.94* 1.2*2.0* 1.0* 1.4* 0.41* 0.28* 3.5* 4.0* Example 42

0.20 0.15 1.0 1.2 2.0 0.24* 0.30* 0.37* 0.44* 0.25* 0.28* 0.19* 0.19*0.16* 0.14* 0.27* 0.20* 0.21* 0.34* 0.22* 0.23* Example 147-h

0.10 0.24 2.8 1.8 0.47* 0.47* 0.48* 0.78* 0.42* 0.47* 0.34* 0.21* 0.22*0.16* 0.94* 0.47* 0.33* 0.58* 0.34* 0.36* Example 39

0.15 0.20 0.37 0.20 0.31* 0.18* 0.23* 0.35* 0.32* 0.22* 0.28* 0.17*0.17* 0.15* 0.32* 0.22* 0.28* 0.36* 0.28* 0.27* Example 43

0.15 0.20 3.9 7.7 0.37* 0.43* 0.33* 0.57* 1.1* 0.36* 0.28* 0.23* 0.25*0.23* 0.43* 0.41* 0.29* 0.59* 0.30* 0.32* Example 147-k

0.20 0.17 2.9 2.9 0.31* 0.32* 0.39* 0.39* 0.40* 0.26* 0.26* 0.15* 0.29*0.16* 0.45* 0.29* 0.35* 0.34* 0.30* 0.15* Example 147-o

0.20 0.16 1.8 1.8 0.77* 0.90* 0.92* 1.1* 0.83* 0.77* 0.63* 0.45* 0.42*0.44* 0.78* 0.71* 0.64* 0.92* 0.76* 0.69* Example 33

0.190 0.140 0.41 0.17* 0.21* 0.26* 0.28* 0.19* 0.21* 0.18* 0.12* 0.19*0.13* 0.20* 0.18* 0.15* 0.15* Example 40

0.23 0.17 1.0 2.0 0.19* 0.28* 0.27* 0.37* 0.29* 0.27* 0.16* 0.18* 0.15*0.18* 0.26* 0.21* 0.20* 0.34* 0.24* 0.21* Example 147-j

0.20 0.21 1.3 0.72 0.20* 0.21* 0.27* 0.30* 0.30* 0.22* 0.17* 0.17* 0.15*0.14* 0.37* 0.25* 0.17* 0.26* 0.21* 0.20* Example 147-i

0.20 0.21 0.61 2.2 1.2 0.30* 0.34* 0.30* 0.45* 0.31* 0.33* 0.24* 0.27*0.17* 0.18* 0.39* 0.26* 0.23* 0.41* 0.23* 0.21* Example 12

0.230 4.5 6.2 3.3 7.1 8.6 11 7.3 8.5 16 18 5.6 3.5 5.4 5.4 4.4 3.5 3.56.7 Example 5

0.230 (n = 1) 0.4 0.7 0.78* 0.87* 1.3* 1.5* 1.0* 1.1* 1.0* 1.2* 0.35*0.53* 0.47* 0.47* 1.1* 0.7* 0.56* 0.7* Example 44

0.23 0.13 0.34 2.3 0.20* 0.22* 0.24* 0.27* 0.22* 0.22* 0.16* 0.17* 0.15*0.09* 0.28* 0.21* 0.16* 0.22* 0.16* 0.16* Example 147-ad Correctstructure

0.28 0.19 3.0 3.2 0.64* 0.64* 0.87* 1.0* 0.79* 0.70* 0.53* 0.58* 0.39*0.43* 0.82* 0.62* 0.48* 0.86* 0.54* 0.62* Example 147-v

0.24 0.24 2.0 3.4 0.63* 1.2* 1.0* 1.3* 0.76* 0.83* 0.58* 0.77* 0.50*0.63* 1.9* 1.1* 0.85* 1.1* 0.52* 0.57 Example 147-l

0.26 0.17 0.28 2.0 2.7 1.3 0.33* 0.29* 0.46* 0.46* 0.37* 0.40* 0.26*0.19* 0.26* 0.19* 0.48* 0.43* 0.31* 0.41* 0.30* 0.29* Example 147-t

0.25 0.16 0.34 2.2 1.7 0.37* 0.37* 0.41* 0.69* 0.42* 0.48* 0.31* 0.36*0.30* 0.28* 0.71* 0.46* 0.37* 0.45* 0.33* 0.38* Example 147-p

0.30 0.11 0.36 3.1 3.9 0.57* 0.60* 0.59* 0.68* 0.71* 0.72* 0.45* 0.48*0.39* 0.34* 0.91* 0.68* 0.46* 0.66* 0.54* 0.54* Example 41

0.30 0.14 0.34 0.75 1.4 0.29* 0.32* 0.35* 0.36* 0.32* 0.31* 0.25* 0.21*0.19* 0.19* 0.38* 0.29* 0.27* 0.42* 0.29* 0.23* Example 25

0.260 6.4 6.9 1.0 2.7 4.5 4.3 2.6 3.0 4.0 3.7 1.9 0.85 0.95 1.1 1.7 0.951.7 Example 147

0.268 5.7 6.1 5.1* 3.2* 5.6* 6.0* 2.8* 2.0* 5.7* 3.5* 2.7* 2.6* 5.2*1.9* 3.2* 2.3* 3.1* 5.7* Example 147-e

0.34 0.23 0.46 2.7 4.6 0.58* 0.30* 0.62* 0.60* 0.59* 0.30* 0.34* 0.32*0.35* 0.30* 0.58* 0.50* 0.47* 0.35* 0.35* 0.41* 816348ta

0.32 0.12 7.4 7.1 0.43* 0.29* 0.38* 0.35* 0.40* 0.30* 0.32* 0.25* 0.27*0.22* 0.40* 0.26* 0.28* 0.32* 0.31* 0.32* Example 23

2 0.95 0.76 4 2.7* 2.6* 2.5* 2.7* 3.1* 3.5* 3.0* 3.3* 2.5* 2.4* 2.3*2.3* 2.9* 2.8* 2.7* 2.8* 2.3* 2.5* 2.3* 2.6* 2.6* 2.1* 2.1* 3.1* 2.7*2.5* 2.2* 3.1* 3.2* 3.0* 3.0* Example 147-g

0.33 0.29 3.5 2.0 0.29* 0.31* 0.30* 0.41* 0.31* 0.29* 0.18* 0.13* 0.19*0.14* 0.32* 0.26* 0.21* 0.39* 0.22* 0.25* Example 147-n

0.16 0.34 0.44 1.6 3.1 0.81* 0.72* 0.89* 1.0* 0.71* 0.64* 0.44* 0.32*0.39* 0.33* 1.1* 0.80* 0.73* 0.93* 0.60* 0.59* Example 147-x

0.32 0.32 3.8 3.9 0.85* 0.67* 0.75* 0.92* 0.72* 0.60* 0.59* 0.62* 0.44*0.45* 1.0* 0.70* 0.54* 0.65* 0.49* 0.53* Example 147-a

0.41 0.097 0.44 2.9 2.1 0.35* 0.34* 0.42* 0.408 0.32* 0.32* 0.20* 0.31*0.17* 0.17* 0.32* 0.33* 0.24* 0.34* 0.22* 0.33* Example 17

0.350 3.1 6.4 6.1 7.9 6.8 6.8 9.9 6.8 7.5 5.3 5.8 4.0 3.6 6.9 Example 22

0.37 0.37 0.4 1.3 0.57 4.2* 8.2* 10* 11* 4.0* 4.4* 3.9* 5.3* 2.6* 6.0*2.7* 2.8* 2.5* 2.3* 3.7* 7.6* Example 147-ac

0.17 0.37 0.53 0.40 3.3 1.2 0.79* 0.75* 0.97* 1.1* 0.61* 0.66* 0.47*0.62* 1.4* 1.0* 0.78* 0.82* 0.71* 0.66* Example 31

0.4 0.4 0.1 0.1 2.1* 2.4* 3.1* 2.6* 2.4* 2.5* 1.4* 1.7* 1.6* 2.1* 2.4*1.8* 2.3* 1.9* 1.9* 1.8* Example 147-c

0.56 0.27 0.45 0.67 0.60 0.23* 0.27* 0.33* 0.34* 0.32* 0.30* 0.19* 0.20*0.18* 0.24* 0.30* 0.32* 0.22* 0.33* 0.21* 0.30* Example 147-r

0.09 0.58 0.55 0.61 7.2 4.3 0.31* 0.48* 0.60* 0.65* 0.49* 0.47* 0.32*0.38* 0.33* 0.33* 0.62* 0.48* 0.39* 0.55* 0.45* 0.40* Example 147-f

0.51 0.22 0.67 1.1 2.1 0.41* 0.38* 0.50* 0.49* 0.40* 0.34* 0.31* 0.25*0.30* 0.21* 0.67* 0.36* 0.36* 0.45* 0.31* 0.29* Example 46

0.50 0.45 20 0.46* 0.53* 0.61* 0.62* 0.53* 0.44* 0.44* 0.46* 0.28* 0.33*0.35* 0.58* 0.39* 0.46* 0.36* 0.49* Example 28

0.480 2.2 2.6 5.6 11 12 14 12 13 >20 >20 1.9 6.1 7.7 4.8 6.4 6.4 9.1Example 20

0.497 4.8* 11* 7.6* 13* 5.6* 4.8* 7.5* 7.9* 6.5* 13* Example 36

0.52 (n = 1) 4.5 3.2* 4.2* 2.2* 4.0* 4* 3.1* 3.1* 5.6* 3.1* 3.6* 3.1*3.1* 3.8* 5.4* 3.4* Example 19

0.540 (n = 1) 20 15* 14* 20* 18* 18* 14* 12* 10* 22* 13* 12* 15* 14* 14*14* 13* Example 147-ab

0.25 0.90 4.5 2.7 0.62* 0.70* 0.84* 0.91* 0.73* 0.62* 0.43* 0.45* 0.33*0.39* 0.74* 0.64* 0.69* 0.69* 0.59* 0.60* Example 147-y

0.51 0.67 5.4 4.8 0.34* 0.35* 0.47* 0.55* 0.41* 0.38* 0.32* 0.35* 0.16*0.29* 0.40* 0.45* 0.35* 0.46* 0.33* 0.35* Example 6

0.690 (n = 1) 0.3 0.7 6.2* 6.4* 14* 11* 13* 7.7* 5.4* 4.7* 7.2* 6.3*9.6* 6.4* 8.2* 7.8* 7.9* Example 37

0.690 (n = 1) 5.2 3.0* 3.0* 3.0* 3.4* 3.2* 2.7* 3.2* 1.8* 2.5* 1.7* 1.6*1.3* 1.3* 1.3* 1.3* 1.7* 1.5* 2.3* 2.8* 2.5* 2.7* 2.6* 3.0* Example147-d

0.89 0.53 0.75 64 0.47* 0.42* 0.69* 0.94* 0.44* 0.34* 0.38* 0.52* 0.23*0.25* 0.34* 0.36* 0.66* 0.66* 0.69* 0.58* Example 147-z

0.72 1.0 7.9 5.7 0.37* 0.35* 0.50* 0.57* 0.43* 0.44* 0.38* 0.46* 0.18*0.30* 0.34* 0.42* 0.33* 0.44* 0.28* 0.36* Example 18

1.0 (n = 1) 1.4 Example 45

1.1 0.90 6.7 13 0.89* 0.71* 0.96* 0.75* 0.71* 0.55* 0.53* 0.48* 0.46*0.32* 1.3* 0.71* 0.63* 0.74* 0.51* 0.46* Example 147-b

1.2 0.92 2.4 4.5 0.64* 0.73* 0.99* 0.95* 0.65* 0.61* 0.48* 0.62* 0.42*0.40* 0.92* 0.82* 0.63* 0.78* 0.46* 0.61* Example 30

1.40 (n = 1) 2.4 Example 147-aa

1.6 2.6 10 8.4 2.5* 3.1* 5.8* 4.9* 2.8* 2.3* 4.0* 2.9* 4.1* 3.6* 2.7*2.9* 3.8* 4.6* 4.4* 4.3* Example 4

19.4 46 >100 Example 24

27.1 4.6 10 107,446 roscovitine

0.31 36 13 >20 157 >20 51 >20 18 >20 14 >20 13 >20 18 18 18 >20Olomoucine

5 >1000 35 35 53 58 62 63 69 69 50 76 55 >100 Flavopiridol

0.130 0.017 0.0 6 0.095 0.17 0.1 0.08 0.08 0.07 0.08 Example 35

0.49 0.14 9.4 7.7 2.9 1.9 2.1 1.9 5.7 4.0 n = 2 n = 1 n = 1 n = 1 n = 1n = 1 n = 1 n = 1 n = 1 n = 1

What is claimed is:
 1. A compound of the formula

wherein R is selected from the group consisting of R2, R2NH—, orR3R4N—R5— wherein R2 is selected from the group consisting of C₉-C₁₂alkyl,

 wherein each R6 is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m)-phenyl, wherein mis an integer 0-8; x is an integer 1-8; n is an integer 1-8; Z isselected from the group consisting of phenyl, heterocycle, cycloalkyl,and naphthyl, where heterocycle is piperidinyl, pyridinyl, isoxazolyl,tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl,benzimidazolyl, thiazolyl, thiophene, furanyl, indolyl,1,3-benzodioxolyl, tetrahydropyranyl, imidazolyl, tetrahydrothiophene,pyranyl, dioxanyl, pyrrolyl, pyrimidinyl, pyrazinyl, triazinyl,oxazolyl, purinyl, quinolinyl, or isoquinolinyl; and M is selected fromthe group consisting of hydrogen, C₁-C₄ alkyl,

wherein each R6′ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′)-phenyl, whereinm′ is an integer 0-8; n′ is an integer 0-8; x′ is an integer 1-8; Q ishydrogen or C₁-C₄ alkyl; and Z′ is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthyl, where heterocycle ispiperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl, pyrrolidinyl,morpholinyl, piperazinyl, benzimidazolyl, thiazolyl, thiophene, furanyl,indolyl, 1,3-benzodioxolyl, tetrahydropyranyl, imidazolyl,tetrahydrothiophene, pyranyl, dioxanyl, pyrrolyl, pyrimidinyl,pyrazinyl, triazinyl, oxazolyl, purinyl, quinolinyl, or isoquinolinyl;and  wherein each C₉-C₁₂ alkyl or Z is optionally substituted with 1 to3 substituents, which may be the same or different, and which areselected from the group consisting of D, E,

 wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; each E isindependently selected from the group consisting of Hal, OH, C₂-C₆alkenyl, and C₁-C₈ alkyl; b is an integer 0-2; Z″ is selected from thegroup consisting of phenyl, heterocycle, cycloalkyl, and naphthyl, whereheterocycle is piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl,pyrrolidinyl, morpholinyl, piperazinyl, benzimidazolyl, thiazolyl,thiophene, furanyl, indolyl, 1,3-benzodioxolyl, tetrahydropyranyl,imidazolyl, tetrahydrothiophene, pyranyl, dioxanyl, pyrrolyl,pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, purinyl, quinolinyl, orisoquinolinyl; each R6″ is independently selected from the groupconsisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m″)-phenyl, wherein m″ is an integer 0-8; n″ is an integer 0-8;x″ is an integer 1-8; and M′ is selected from the group consisting ofhydrogen, C₁-C₄ alkyl,

wherein each R6′″ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′″)-phenyl, whereinm′″ is an integer 0-8; n′″ is an integer 0-8; x′″ is an integer 1-8; Q′is hydrogen or C₁-C₄ alkyl; and Z′″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl, whereheterocycle is piperidinyl, pyridinyl, isoxazolyl, tetrahydrofuranyl,pyrrolidinyl, morpholinyl, piperazinyl, benzimidazolyl, thiazolyl,thiophene, furanyl, indolyl, 1,3-benzodioxolyl, tetrahydropyranyl,imidazolyl, tetrahydrothiophene, pyranyl, dioxanyl, pyrrolyl,pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, purinyl, quinolinyl, orisoquinolinyl,  wherein the groups M′ and Z″ may be optionallysubstituted with the groups D′, E′ or

 provided M′ is not hydrogen, wherein each R6″″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is aninteger 0-8; Q″ is hydrogen or C₁-C₄ alkyl or phenyl; each D′ isindependently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C₁-C₄ alkoxy; each E′ is independently selectedfrom the group consisting of Hal, OH, and C₁-C₈ alkyl; R3 and R4 areselected from the group consisting of hydrogen, C₁-C₄ alkyl and(CH₂)_(y)-phenyl, wherein y is an integer 0-8, with the proviso that R3and R4 not both be hydrogen; R5 is C₁-C₈ alkylene; and R1 is isopropyl,and the pharmaceutically acceptable salts, optical isomers, and hydratesthereof, with the proviso that when R2 is the group

 wherein n is 1 or greater; R6 is hydrogen, C₁-C₄ alkyl, or(CH₂)_(m)-phenyl; and Z is phenyl, heterocycle, or cycloalkyl, that Z issubstituted with 1 to 3 substituents, which may be the same ordifferent, and which are selected from the group consisting of

 wherein D, b, R6″, x″, n″, M′, and Z″ are as previously defined.
 2. Thecompound according to claim 1 wherein R is R2, wherein R2 is C₉-C₁₂alkyl, which may be optionally substituted with 1 to 3 substituents,which may be the same or different, and which are selected from thegroup consisting of D, E,

wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; each E isindependently selected from the group consisting of Hal, OH, C₂-C₆alkenyl, and C₁-C₈ alkyl; b is an integer 0-2; Z″ is selected from thegroup consisting of phenyl, heterocycle, cycloalkyl, and naphthyl, eachR6″ is independently selected from the group consisting of hydrogen,C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m″)-phenyl, wherein m″ is aninteger 0-8; n″ is an integer 0-8; x″ is an integer 1-8; and M′ isselected from the group consisting of hydrogen, C₁-C₄ alkyl,

wherein each R6′″ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′″)-phenyl, whereinm′″ is an integer 0-8; n′″ is an integer 0-8; x′″ is an integer 1-8; Q′is hydrogen or C₁-C₄ alkyl; and Z′″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl, wherein thegroups M′ and Z″ may be optionally substituted with the groups D′, E′ or

 provided M′ is not hydrogen, wherein each R6″″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is aninteger 0-8; Q″ is hydrogen or C₁-C₄ alkyl or phenyl; each D′ isindependently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C₁-C₄ alkoxy; each E′ is independently selectedfrom the group consisting of Hal, OH, and C₁-C₈ alkyl, and thepharmaceutically acceptable salts, optical isomers, and hydratesthereof.
 3. The compound according to claim 1 wherein R is R2, whereinR2 is

wherein each R6 is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m)-phenyl, wherein mis an integer 0-8; x is an integer 1-8; and M is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl,

wherein each R6′ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′)-phenyl, whereinm′ is an integer 0-8; n′ is an integer 0-8; x′ is an integer 1-8; Q ishydrogen or C₁-C₄ alkyl; and Z′ is selected from the group consisting ofphenyl, heterocycle, cycloalkyl, and naphthyl, and the pharmaceuticallyacceptable salts, optical isomers, and hydrates thereof.
 4. The compoundaccording to claim 1 wherein R is R2, wherein R2 is

wherein each R6 is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m)-phenyl, wherein mis an integer 0-8; n is an integer 1-8; Z is naphthyl, wherein Z isoptionally substituted with 1 to 3 substituents, which may be the sameor different, and which are selected from the group consisting of D, E,

wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; each E isindependently selected from the group consisting of Hal, OH, C₂-C₆alkenyl, and C₁-C₈ alkyl; b is an integer 0-2; each R6″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″)-phenyl, wherein m″ is an integer 0-8; x″ is aninteger 1-8; n″ is an integer 0-8; Z″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl; and M′ isselected from the group consisting of hydrogen, C₁-C₄ alkyl,

wherein each R6′″ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′″)-phenyl, whereinm′″ is an integer 0-8; n′″ is an integer 0-8; x′″ is an integer 1-8; Q′is hydrogen or C₁-C₄ alkyl; and Z′″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl, wherein thegroups M′ and Z″ may be optionally substituted with the groups D′, E′ or

 provided M′ is not hydrogen, wherein each R6″″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is aninteger 0-8; Q″ is hydrogen or C₁-C₄ alkyl or phenyl; each D′ isindependently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C₁-C₄ alkoxy; each E′ is independently selectedfrom the group consisting of Hal, OH, and C₁-C₈ alkyl, and thepharmaceutically acceptable salts, optical isomers, and hydratesthereof.
 5. The compound according to claim 1 wherein R is R2, R2 is

wherein each R6 is independently hydrogen or C₃-C₈ cycloalkyl, with theproviso that at least one of R6 is C₃-C₈ cycloalkyl; n is an integer1-8; and Z is phenyl, wherein Z is substituted with 1 to 3 substituents,which may be the same or different, and which are selected from thegroup consisting of D, E,

wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; each E isindependently selected from the group consisting of Hal, OH, C₂-C₆alkenyl, and C₁-C₈ alkyl; b is an integer 0-2; each R6″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″)-phenyl, wherein m″ is an integer 0-8; x″ is aninteger 1-8; n″ is an integer 0-8; Z″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl; and M′ isselected from the group consisting of hydrogen, C₁-C₄ alkyl,

wherein each R6′″ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′″)-phenyl, whereinm′″ is an integer 0-8; n′″ is an integer 0-8; x′″ is an integer 1-8; Q′is hydrogen or C₁-C₄ alkyl; and Z′″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl, wherein thegroups M′ and Z″ may be optionally substituted with the groups D′, E′ or

 provided M′ is not hydrogen, wherein each R6″″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is aninteger 0-8; Q″ is hydrogen, C₁-C₄ alkyl or phenyl; each D′ isindependently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C₁-C₄ alkoxy; each E′ is independently selectedfrom the group consisting of Hal, OH, and C₁-C₈ alkyl, and thepharmaceutically acceptable salts, optical isomers, and hydratesthereof.
 6. The compound according to claim 1 wherein R is R2, R2 is

wherein each R6 is independently selected from the group consisting ofhydrogen, C₁-C₄ alkyl, and (CH₂)_(m)-phenyl, wherein m is an integer0-8; n is an integer 1-8; and Z is phenyl, wherein Z may be optionallysubstituted with 1 to 3 substituents, which may be the same ordifferent, and which are selected from the group consisting of

wherein each D is independently selected from the group consisting oftrifluoromethyl, trifluoromethoxy, and C₁-C₄ alkoxy; b is an integer0-2; Z″ is selected from the group consisting of phenyl, heterocycle,cycloalkyl, and naphthyl; each R6″ is independently selected from thegroup consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and(CH₂)_(m″)-phenyl, wherein m″ is an integer 0-8; x″ is an integer 1-8;n″ is an integer 0-8; and M′ is selected from the group consisting ofhydrogen, C₁-C₄ alkyl,

wherein each R6′″ is independently selected from the group consisting ofhydrogen, C₃-C₈ cycloalkyl, C₁-C₄ alkyl, and (CH₂)_(m′″)-phenyl, whereinm′″ is an integer 0-8; n′″ is an integer 0-8; x′″ is an integer 1-8; Q′is hydrogen or C₁-C₄ alkyl; and Z′″ is selected from the groupconsisting of phenyl, heterocycle, cycloalkyl, and naphthyl, wherein thegroups M′ and Z″ may be optionally substituted with the groups D′, E′ or

 provided M′ is not hydrogen, wherein each R6″″ is independentlyselected from the group consisting of hydrogen, C₃-C₈ cycloalkyl, C₁-C₄alkyl, and (CH₂)_(m″″)-phenyl, wherein m″″ is an integer 0-8; x″″ is aninteger 0-8; Q″ is hydrogen, C₁-C₄ alkyl or phenyl; each D′ isindependently selected from the group consisting of trifluoromethyl,trifluoromethoxy, and C₁-C₄ alkoxy; each E′ is independently selectedfrom the group consisting of Hal, OH, and C₁-C₈ alkyl, and thepharmaceutically acceptable salts, optical isomers, and hydratesthereof.
 7. The compound of claim 6 wherein Z is substituted with D. 8.The compound of claim 7 wherein D is C₁-C₄ alkoxy.
 9. The compoundaccording to claim 8 which is2-[trans-(4-aminocyclohexyl)amino]-6-[(3,4-dimethoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride;2-[trans-(4-aminocyclohexyl)amino]-6-[(2,3-dimethoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride; or2-[trans-(4-aminocyclohexyl)amino]-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purinedihydrochloride.
 10. A method of treating carcinoma selected from thegroup consisting of cervix carcinoma, breast carcinoma, prostatecarcinoma, esophageal carcinoma, small intestine carcinoma, coloncarcinoma, ovary carcinoma, lung carcinoma, comprising administering toa patient in need of said treatment an effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,optionally in combination with the pharmaceutically acceptable carrier.11. A method of treating adenocarcinoma selected from the groupconsisting of cervix adenocarcinoma, breast adenocarcinoma, prostateadenocarcinoma, esophageal adenocarcinoma, small intestineadenocarcinoma, colon adenocarcinoma, ovary adenocarcinoma, lungadenocarcinoma, comprising administering to a patient in need of saidtreatment an effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, optionally in combination withthe pharmaceutically acceptable carrier.
 12. A method of treating adisease condition selected from the group consisting of osteosarcoma,liposarcoma, hemangiosarcoma, carcinosarcoma and reticulum cell sarcomacomprising administering to a patient in need of said treatment aneffective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof, optionally in combination withthe pharmaceutically acceptable carrier.
 13. A method of treatingamelanotic melanoma or melanotic melanoma comprising administering to apatient in need of said treatment an effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof,optionally in combination with the pharmaceutically acceptable carrier.14. A method of preventing apoptosis in neuronal cells in a patient byadministration of a compound according to claim
 1. 15. The methodaccording to claim 14, wherein the apoptosis is induced byantineoplastic agents.
 16. The method according to claim 14, wherein theapoptosis is induced by cerebrovascular disease.
 17. The methodaccording to claim 14, wherein the apoptosis is induced by stroke orinfarction.
 18. A method of protecting method of protecting neuronalcells from apoptosis comprising administering a compound according toclaim
 1. 19. A method of protecting neuronal cells from damage inducedby antineoplastic agents, comprising administering a compound accordingto claim
 1. 20. A composition comprising an assayable amount of acompound of claim 1 in admixture or otherwise in association with aninert carrier.
 21. A pharmaceutical composition comprising an effectivecdk-2 inhibiting amount of a compound of claim 1 in admixture orotherwise in association with one or more pharmaceutically acceptablecarriers or excipients.